Keywords: Data models, Spatio-temporal data modelling, 3D visualization, Open systems

Delivering time-evolving 3D city models for web visualization

Studying and planning urban evolution is essential to understanding the past and designing the cities of the future and can be facilitated by providing means for sharing, visualizing, and navigating in cities, on the web, in space and in time. Standard formats, methods, and tools exist for visualizing large-scale 3D cities on the web. In this article, we go further by integrating the temporal dimension of cities to geospatial web delivery standard formats. In doing so, we enable interactive visualization of large-scale timeevolving 3D city models on the web. A key characteristic of this article lies in the proposed four-step generic approach. First, we design a generic conceptual model of standard formats for delivering 3D cities on the web. Then, we formalize and integrate the temporal dimension of cities to this generic conceptual model. After that, we specify the conceptual model into the 3D Tiles standard at logical and technical specification levels, resulting in an extension of 3D Tiles for delivering time-evolving 3D city models on the web. Finally, we propose an open-source implementation, experiments, and an evaluation of the propositions and visualization rules. We also give access to reproducibility notes allowing researchers to replicate all the experiments.

Introduction

Cities evolve in a continuous manner on various scales in space and time (e.g. roof restoration, construction of a bridge, renovation of a district, etc.). Understanding these changes from the past and planning the future of cities is key to a number of applications such as understanding the urban fabric, representing and managing cultural heritage, performing energy simulations, etc. We, therefore, need to provide solutions to store, query, exchange, visualize, and interact with digital cities in space and time at various granularity levels.

Numerical representations of cities are usually based on models composed of sets of 3D geometric objects, thematic information (e.g., building, vegetation, address, etc.) and of hierarchical relationships between these objects [START_REF] Stadler | Spatio-semantic coherence in the integration of 3D city models[END_REF]Kolbe 2007, Kolbe 2009). These representations effectively express the geometric and thematic dimensions of the city at Vincent JAILLOT, Sylvie SERVIGNE, Gilles GESQUIERE together represents the building better because the approach connects objects across the states of the building and meanwhile retains thematic information describing the changes. City models based on the state-and-transaction representation are called time-evolving 3D city models in the following. While the previous studies proposed many models for time-evolving 3D city models, methods are still lacking to efficiently deliver these large-scale, time-evolving 3D city models on the web in a manner enabling interactive spatio-temporal visualization. To address this challenge, we propose a generic approach based on standards. The proposed approach models the evolution of 3D city models' features based on states and transactions with thematic information describing the changes. In addition, the proposed approach represents changes at various levels of granularity in space and time. Furthermore, the proposed approach enables visualization of large-scale data sets (e.g. at a city scale) and allows users to navigate through the 3D city interactively in space and time. The development of the proposed approach leads to the following contributions and outline:

• Developing a generic conceptual model for delivering 3D cities for web visualization based on standard (section 3.1)

• Formalizing and integrating the temporal dimension of cities to this model (section

3.2)

• Specifying this model at the logical and technical levels by formalizing and extending the 3D Tiles standard (section 4)

• Implementing the proposed approach in open-source web software, evaluating the software's performance and documenting the procedures to ensure reproducibility (section 5)

In the following section, we examine state of the art on delivering 3D city models on the web (section 2.1) and on representing the temporal dimension of urban data (section 2.2).

Then, we present a summary which highlights the limits of current state of the art. (section 2.3). [START_REF] Prieto | Efficient visualization of the geometric information of CityGML: application for the documentation of built heritage[END_REF] adopts the X3D format for delivering 3D city models on the web. However, the X3D format considers only the geometry of city models, discarding the thematic information and hierarchical relationships. Other initiatives have proposed the delivery of CityGML (Open Geospatial Consortium 2012) data on the web (Gesquière andManin 2012, Pispidikis and[START_REF] Pispidikis | CityGML restful web service: automatic retrieval of CityGML data based on their semantics. Principles, guidelines and BLDG conceptual design[END_REF] but fall short of optimal delivery when used by web clients due to two key reasons. First, CityGML is designed for data modelling and exchange [START_REF] Kolbe | Representing and exchanging 3D city models with CityGML[END_REF], not visualization or user interaction which are important for webclient applications. In addition, CityGML is not based on web-friendly data formats (e.g. JSON), which makes it harder to use in a web context.

State of the art

Delivering 3D city models on the web

The Open Geospatial Consortium (OGC) proposes a set of web services to deliver geospatial data on the web (WFS1 , WMS2 , etc.). While, WFS could be used to deliver 3D city models on the web, WFS is unsuitable for large-scale 3D data sets (Open Geospatial Consortium, 2018b). Later, two community standards have been proposed for delivering heterogeneous 3D geospatial data sets: 3D Tiles (Open Geospatial Consortium, 2018a) and I3S (Open Geospatial Consortium, 2017b). These standards share concepts and characteristics: represent the geometry (3D polygonal models or 3D point clouds) and thematic information of geospatial data (Open Geospatial Consortium 2018b); use spatial indexing methods to organize large data sets; and adopt JSON and binary representations for efficient web-based operations. The main differences between these standards lie in their ways of representing data at the technical specification level. For instance, I3S has a unified way of representing features of the city whereas 3D Tiles include different formats: Batched 3D Model (b3dm) and Instanced 3D Model (i3dm) (which are based on glTF) for 3D polygonal models and Point Cloud (pnts) for 3D point clouds. [START_REF] Schilling | Using glTF for streaming CityGML 3D city models[END_REF] extends the 3D Tiles with the hierarchical relationships of 3D city models to enable the delivery of complete 3D city models (geometry, thematic and hierarchical relationships) However, neither 3D Tiles nor I3S integrates the temporal dimension of cities.

In addition to these formats, the 3D Portrayal Service OGC standard provides an interface for 3D geospatial data to support queries about a 3D scene in a web context with a generic and standard approach. Responses to a query may be in any format including 3D Tiles and I3S [START_REF] Koukofikis | Interoperable visualization of 3D city models using OGC's standard 3D Portrayal Service[END_REF]. Hence, either 3D Tiles or I3S can provide a common interface for delivering 3D city models on the web. [START_REF] Chaturvedi | A requirement analysis on extending semantic 3D city models for supporting time-dependant properties[END_REF] identify two categories of temporal changes related to 3D city models. The first type of changes concerns the evolution of structural elements of the city (e.g., building, bridges, etc.). The second type of change considers properties external to city models and the property's varying values over time (e.g., time series such as solar irradiance or electricity consumption of a building).

Representing the temporal dimension of urban data

With the growing need for modelling and visualization of a city and the city's evolution over time, researchers have proposed a 4D (3D geometry and time) digital reconstruction of a specific monument [START_REF] Rizvic | Visualization and multimedia presentation of cultural heritage[END_REF], district [START_REF] Schindler | 4D cities: analyzing, visualizing, and interacting with historical urban photo collections[END_REF] or city [START_REF] Yano | Virtual Kyoto: 4DGIS comprising spatial and temporal dimensions[END_REF] along with visualization methods and tools. However, these proposals represent the temporal dimension as a collection of states of the dataset (i.e., independent representations of the data at different timestamps or for different periods of time, c.f. representation of states in Figure 1). As such, none of the proposals considers the thematic information or the hierarchical relations between objects, which are a key element for numerous applications [START_REF] Döllner | Virtual 3D city models as foundation of complex urban information spaces[END_REF][START_REF] Biljecki | Applications of 3D city models: State of the art review[END_REF].

Other formalizations are based on modelling the states of geospatial objects and the transitions across these states. [START_REF] Renolen | Modelling spatiotemporal information: The spatiotemporal object model[END_REF] proposes a formalization of six possible transitions occurring to geospatial features (e.g., buildings). Figure 2 illustrates these six basic types of transitions. In this formalization, a transition can either consist in a creation (e.g., construction of a new building), alteration (e.g., roof restoration), cessation (e.g., bridge destruction), reincarnation (e.g., destruction and reconstruction of building), merge (e.g., two buildings are joined together to form one building) or split (e.g., a building is separated into two parts to form two distinct buildings). [START_REF] Stefani | Maquettes numériques spatio-temporelles d'édifices patrimoniaux: maquettes numériques spatio-temporelles d'édifices patrimoniaux[END_REF] extended these types of transitions from an architectural and urban point of view, giving seventeen possible types of transitions between two states of a heritage building.

Figure 2. Six basic types of transitions between geospatial objects [START_REF] Renolen | Modelling spatiotemporal information: The spatiotemporal object model[END_REF]. [START_REF] Chaturvedi | Managing versions and history within semantic 3D city models for the next generation of CityGML[END_REF] extends the CityGML standard to represent the temporal dimension of 3D city models to represent the states of geospatial features and the transitions between these states (called Transactions). As this work is currently being standardized for CityGML 3.0, we will also use the term transaction to conform with the terminology used in [START_REF] Renolen | Modelling spatiotemporal information: The spatiotemporal object model[END_REF] and [START_REF] Stefani | Maquettes numériques spatio-temporelles d'édifices patrimoniaux: maquettes numériques spatio-temporelles d'édifices patrimoniaux[END_REF]. There are other related terms suggested in the literature. [START_REF] Chaturvedi | Managing versions and history within semantic 3D city models for the next generation of CityGML[END_REF] introduce the concept of Versions to and VersionTransitions. A Version is a collection of temporal geospatial features (i.e. having a time-span). A VersionTransition is a collection of Transactions where each Transaction expresses the changes that relate two geospatial features. In addition, Transactions can refer to changes at various levels of spatial granularity, which is one of the requirements in our development of time-evolving 3D-City web delivery and visualization. For instance, a transaction can refer to a building modification, a roof restoration, or a door change, etc. However, the method by [START_REF] Chaturvedi | Managing versions and history within semantic 3D city models for the next generation of CityGML[END_REF] is based on CityGML, which is unfit for data delivery and interactive visualization on the web, as explained in section 2.1. In addition, [START_REF] Chaturvedi | Managing versions and history within semantic 3D city models for the next generation of CityGML[END_REF] consider only three types of Transactions are possible: insert, delete, and replace, whereas [START_REF] Renolen | Modelling spatiotemporal information: The spatiotemporal object model[END_REF] and [START_REF] Stefani | Maquettes numériques spatio-temporelles d'édifices patrimoniaux: maquettes numériques spatio-temporelles d'édifices patrimoniaux[END_REF] have proved that more transactions are needed to fully describe the evolution of city components. [START_REF] Samuel | UrbanCo2Fab: Comprehension of concurrent viewpoints of urban fabric based on GIT[END_REF] extend the work by [START_REF] Chaturvedi | Managing versions and history within semantic 3D city models for the next generation of CityGML[END_REF] to represent various possible scenarios of the evolution of a city and to store, query, and update versions, version transitions and transactions of scenarios of city evolution. However, this solution emphasizes managing the evolution of the city (e.g., to enable historians to update information on the city's evolution), not delivering data on the web for visualization and interaction.

Summary

The goal of the work presented in this paper is to deliver large-scale, time-evolving 3D city models on the web in a way allowing for interactive spatio-temporal visualization, with an approach based on standards. Time-evolving 3D city models have geometric (3D), thematic and temporal (states and transactions) dimensions with hierarchical relationships among objects. None of the standards and methods reviewed in this section integrate all these aspects. However, the three established standards (CityGML, 3D Tiles and I3S) present some of these characteristics. They are compared with our needs in Table 1. While CityGML can model all the dimensions of time-evolving 3D city models, the methods to deliver CityGML data on the web are unsatisfactory (see section 2.1). We, therefore, focus our work on 3D Tiles and I3S. Although they do not integrate all the aspects of time-evolving 3D city models, extensions are possible to meet our needs. Given the conceptual similarities between 3D Tiles and I3S, we first propose a generic conceptual model in UML (Gen3DCity model, section 3.1) based on the two standards so that our proposed approach can be implemented on either of the format, I3S or 3D Tiles. We then propose a formalization of the temporal dimension of cities and integrate the formal temporal model into Gen3DCity (Gen4DCity model, section 3.2). This formalization is based on the concepts proposed by [START_REF] Renolen | Modelling spatiotemporal information: The spatiotemporal object model[END_REF], [START_REF] Stefani | Maquettes numériques spatio-temporelles d'édifices patrimoniaux: maquettes numériques spatio-temporelles d'édifices patrimoniaux[END_REF] and [START_REF] Chaturvedi | Managing versions and history within semantic 3D city models for the next generation of CityGML[END_REF]. However, we modify and extend these concepts to propose a more generic formalization of the temporal dimension. After that, we specify Gen4DCity at logical and technical specification levels into the 3D Tiles standard (section 4). Table 1 shows that 3D Tiles format is more suited to our requirements than I3S since an extension of 3D Tiles3 can represent hierarchical relations of 3D city models [START_REF] Schilling | Using glTF for streaming CityGML 3D city models[END_REF]. However, the first two steps of generic conceptual modelling are able to map our model to I3S.

Generic UML models

Conceptual modeling for delivering 3D city models on the web generalizing 3D

Tiles and I3S

Figure 3 presents Gen3DCity: a generic conceptual model for delivering 3D city models on the web, that is to say that we use UML Class Diagrams at Conceptual level and not at Specification or Implementation level (Embley 2011[START_REF] Fowler | UML Distilled: A Brief Guide to the Standard Object Modeling Language (3rd Edition)[END_REF]. This model is an abstraction of the 3D Tiles and I3S standards. The names of the entities are independent of 3D Tiles and I3S and have been chosen to match their concepts with an effort to be as generic as possible.

Figure 3. Gen3DCity: a generic UML conceptual model for delivering 3D city models on the web, generalizing 3D Tiles and I3S standards.

Geospatial Features (e.g., building, roof, bridge, etc.) can have a Geometry (e.g., point cloud, polygonal model, etc.) and Thematic Attributes (e.g., owner). These Geospatial Features are organized according to a spatial indexing method (e.g., quadtree, octree, etc.).

The resulting index is represented by a set of related Spatial Nodes (that is to say nodes computed according to spatial criteria), most frequently representing a tree. 3D Tiles and I3S

both allow multiple indexes that can be grouped to a root object. This root object is represented by a Set in our model. In the case of 3D Tiles, a Spatial Node can either directly reference a set of Geospatial Features or another new index (i.e., another Spatial Node hierarchy). In the case of I3S, indexes are grouped into layers (representing a data layer, e.g., a building layer), which constitute a scene. Finally, 3D Tiles and I3S can represent the geospatial data at various levels of details in a Spatial Nodes hierarchy: a child Spatial Node can be a refinement of its parent.

The representation of geospatial features, spatial nodes, sets, and spatial-nodes hierarchy expresses the shared concepts of 3D Tiles and I3S and can work with the two standards at the conceptual level (e.g., to extend them) without being tied to one or the other.

Moreover, the representation can support implementation choices in either standard. In the following section, we formalize the temporal dimension of cities and integrate it into this representation. Extensions to Gen3DCity take four steps. First, we add a Time-span 4 entity specifying the interval of existence between two dates in the real world for each Geospatial Feature to note the feature's valid time (e.g. a building built in 1975 and destroyed in 2012). Spatial Nodes can also be associated with a Time-span to use spatio-temporal indexing methods [START_REF] Theodoridis | Specifications for efficient indexing in spatiotemporal databases[END_REF][START_REF] Hadjieleftheriou | Efficient indexing of spatiotemporal objects[END_REF][START_REF] Mokbel | Spatio-temporal access methods[END_REF] or temporal indexing methods (Bertino et al. 2012). Organizing spatio-temporal features using a spatial indexing method is easy to implement but may not be optimal. We decide to leave the choice of type of indexing method (spatial, spatio-temporal or temporal) to the user, as the user preference is highly dependent on the data and on the application use case. A Set can also be associated with a Time-span for the entire collection of spatial nodes.

Integration of the temporal dimension for delivering time-evolving 3D city models on the web

Secondly, we introduce the Transaction entity to represent the changes between geospatial features. A Transaction is composed of a description and tags and is subject to two specifications: PrimaryTransaction and TransactionAggregate. The idea behind this proposition is to combine primary transactions for complex transactions. PrimaryTransaction entities have a type attribute which can have one of the following five values: creation, demolition, modification, union or division. We consider these five types as primary types, individually or in combination, capable of modeling other types of transactions encountered in the literature. For instance, [START_REF] Renolen | Modelling spatiotemporal information: The spatiotemporal object model[END_REF] proposes six types of transaction between geospatial features (Figure 2), five of which corresponds to the primary types we propose.

However, the sixth one (reincarnation) can be modeled using a TransactionAggregate composed of two PrimaryTransactions of types demolition and creation (Figure 5).

PrimaryTransactions and TransactionAggregates adequately capture all the transactions types proposed by [START_REF] Stefani | Maquettes numériques spatio-temporelles d'édifices patrimoniaux: maquettes numériques spatio-temporelles d'édifices patrimoniaux[END_REF]. The proposed treatment of transactions has two main advantages.

First, the proposed treatment is more generic than the current solutions because it doesn't restrict the transactions to a limited set of predefined types. Secondly, the proposed treatment of transactions can represent Transactions at different levels of detail, such as the reincarnation type proposed by [START_REF] Renolen | Modelling spatiotemporal information: The spatiotemporal object model[END_REF] at a macro level of detail (TransactionAggregate) or at a finer grain, with PrimaryTransactions of the types demolition and creation (Figure 5). In section 4, we specify Gen4DCity at the logical and specification levels in the 3D Tiles standard format. on the property and on the format (b3dm, i3dm, etc.).

Specification into 3D Tiles

3D Tiles logical model and temporal extension

We integrate the formalization of the temporal dimension proposed in Gen4DCity with the entities in gray. Most of the concepts have been integrated by direct mapping from Gen4DCity thanks to the abstract modelling work done in section 3.1 and to the mapping of Gen3DCity to Logic3DCity described above. VersionTransition, Version and Transaction are aggregated in the Tileset since they are related to Features across the Tileset (i.e. that can be in different Tiles). The Spatial Node's Time-span (from Gen4DCity) is aggregated in the Bounding Volume and not in the Tile (which could have been done by direct mapping since Spatial Node is mapped to Tile). This way not only can the boundingVolume attribute of the Tile have a Time-span, but also its viewerRequestVolume and the boundingVolume attribute of TileContent. The boundingVolumes make it possible to index Features using spatio-temporal indexing methods. The viewerRequestVolume makes it possible to show the content of a Tile only when the display date (date at which the data is displayed to the user) is inside its Timespan.

In section 4.2, we propose an extension of 3D Tiles for time-evolving 3D city models at technical specification level. We name it 3DTiles_temporal (following the naming convention of 3D Tiles).

Extension at technical specification level

3D Tiles contains concepts named extension and extra. The 3DTiles_temporal extension specification is described with JSON schemas, which we make available online (see Data and codes availability statement). It uses the Extension concept. This way, the core of the standard is not modified, but there is still an impact on users of 3D Tiles.

The specification is composed of three Extension objects respectively aggregated in Tileset, BoundingVolume and BatchTable. The Tileset has a startDate and an endDate and stores versions, versionTransitions and transactions. The extension of the BoundingVolume also has a startDate and an endDate to allow the representation of 4D bounding volumes. The BatchTable is where the thematic attributes of features are stored. We extend it with two arrays representing the time of existence of each Feature, namely startDates and endDates.

The BatchTable also holds an array of identifiers of Features enabling them to be identified in transactions and versions. This specification results from models previously presented and more specifically from Logic4DCity.

The models proposed in this section allow to model the temporal dimension of 3D city models by extending the 3D Tiles standard format. In particular, they allow to keep track of the evolution of 3D city models' features at various granularity levels and to add thematic information to these, which was some of the challenges stated in the introduction of this paper.

Implementation and evaluation

In this section we present an implementation allowing to deliver and visualize time-evolving 3D city models on the web with the 3DTiles_temporal extension proposed in this paper. We start with a presentation of the software implementation (section 5.1). We continue with an evaluation of our propositions (section 5.2), demonstrating that they allow to achieve interactive spatio-temporal visualization of large-scale time-evolving 3D city data sets on the web. We finish with the proposition of visualization rules for urban evolution visualization and apply them for the visualization of a time-evolving 3D city model (section 5.3). Complete notes to reproduce the results of this section are provided in the Data and codes availability statement.

Software implementation

We implemented the temporal extension of 3D Tiles proposed in this paper in a 4-tier web architecture. This implementation is fully open source and allows for the creation, delivery and visualization of time-evolving 3D city models on the web. It is composed of two main processes.

The first process enables the creation of time-evolving 3D city models in 3D Tiles with the temporal extension proposed in this article. It is implemented in Py3DTiles 6 which is a software component making it possible to convert geospatial data to 3D Tiles. This process is composed of two parts. The first one is an implementation of the temporal extension proposed in this article and it follows the technical specification of the extension. The second part (City Temporal Tiler7 ) allows to go from 3DCityDB [START_REF] Yao | 3DCityDB-a 3D geodatabase solution for the management, analysis, and visualization of semantic 3D city models based on CityGML[END_REF] databases holding timestamped city models and from a list of changes between the buildings of these city models to a 3D Tiles + temporal extension dataset. The list of changes between the buildings of timestamped city models can be computed with an algorithm allowing to detect geometric changes between buildings at different timestamps [START_REF] Pedrinis | Change detection of cities[END_REF]. This process is implemented in the 3DUSE8 software component. It is not detailed here as it is more of a preprocessing step to obtain a dataset rather than directly allowing to prove the validity of the contributions proposed in this article.

The second process enables delivery and visualization of 3D Tiles + temporal extension datasets on the web. Delivering these time-evolving 3D city models can be done using any web server such as an http web server for instance. The client-side processing of the dataset has been implemented in UD-Viz9 (Urban Data Visualization). UD-Viz is a web client for geospatial data visualization and navigation, based on the geospatial data visualization framework iTowns10 .

Since the formalization of the temporal dimension has been integrated to 3D Tiles as an extension (following the recommendations of the standard), it could be implemented into other software components supporting 3D Tiles (e.g. Cesium11 ). This software implementation allows to run experiments for evaluating our contributions (section 5.2).

Experiments and evaluation

The objectives of this section are to evaluate the scalability and the interactivity of the 3DTiles_temporal extension. In particular, we show that it allows to visualize large-scale time-evolving 3D city models while allowing interactive spatio-temporal navigation. First, we present the data set and the different standard representations chosen for this evaluation (section 5.2.1). Secondly, we evaluate the interactivity of the spatio-temporal navigation (section 5.2.2).

Datasets comparison

In order to evaluate the 3DTiles_temporal extension, we use a data set representing the buildings of the city of Lyon, France (48 km²) between 2009 and 2015. We stored this data set in three different ways: in CityGML, in 3D Tiles and in 3D Tiles extended with 3DTiles_temporal. We name these representations DS-CityGML, DS-3DTiles and DS-3DTiles-Tmp respectively. The evaluation takes place on DS-3DTiles and DS-3DTiles-Tmp.

DS-CityGML is the input data used to create them and it is only added in the comparison of this section for information purposes.

DS-CityGML is composed of three independent snapshots of the city of Lyon (2009, 2012 and 2015). The original data has been downloaded from the Grand Lyon open data website12 . However, it has some quality issues. In particular, it has syntax errors, the data structure and the version of CityGML are not the same between vintages (2009,2012,2015).

A pre-processing step allowed to correct these issues. In addition, DS-CityGML has been simplified by removing textures coordinates and generic thematic attributes that are not included in DS-3DTiles and DS-3DTiles-Tmp.

DS-3DTiles is composed of the same three independent snapshots (2009, 2012 and 2015) of the buildings of the city of Lyon than DS-CityGML. It has been created by converting each snapshot of DS-CityGML into the 3D Tiles format using the City Tiler process13 of py3DTiles (transforming CityGML data sets to 3D Tiles). 3D Tiles (DS-3DTiles) and in 3D Tiles extended with 3DTiles_temporal (DS-3DTiles-Tmp).

DS-3DTiles-

Table 2 shows that the size of DS-3DTiles-Tmp is 7.3 times smaller than DS-CityGML [2009;2015]).

This memory gain is a great improvement, as reducing the size of the dataset makes it possible both to reduce the memory footprint for the client and the network transmission time, which are limiting factors for scalability.

Spatio-temporal navigation evaluation

We recorded the time for loading, rendering and navigating in DS-3DTiles and DS-3DTiles-Tmp to evaluate the interactivity of the spatio-temporal navigation. To this end, they have been visualized in UD-Viz. The following experiments have been conducted with an Intel Core i7-4790K CPU @ 4.00GHZ and with 32GB of RAM. The data have been served using a local web server and visualized with a Firefox 67.0 web browser. In the current implementation, the data is indexed according to a kd-tree. We believe that implementing a spatio-temporal indexing method, such as an HR-Tree [START_REF] Nascimento | Towards historical R-trees[END_REF] for instance, may reduce the time for loading and rendering DS-3DTiles-Tmp, especially for displaying the first state (from nothing displayed to a first state). Such an indexing method would indeed allow to better organize the features along the temporal axis and therefore reduce the number of features that are transmitted to the client for the first display state. In addition, it would also allow to implement a promising approach to deliver the temporal evolution as a progressive stream.

Finally, our temporal extension allows to access information between the three temporal states of DS-3DTiles (2009, 2012and 2015). This idea is depicted in Figure 9 where we can see that the temporal extension allows to navigate in transitory states between two temporal snapshots. The measured time on this figure show that this navigation can be done at a fraction of the cost than with classic 3D Tiles. Therefore, our extension allows to greatly enhance navigation in time.

Figure 9. Temporal navigation comparison between 3D Tiles and 3D Tiles with temporal extension.

5.3.Visualize urban evolution in 3D and on the web

In this section, we propose visualization rules for displaying time-evolving 3D city models represented in 3D Tiles extended with 3DTiles_temporal. The purpose of these visualization rules are to highlight the changes in the city to help understanding urban evolution. Our proposition is to represent features' known states in a reference color (light gray in this example) and to showcase transactions between these states. Generally, transactions span for a certain amount of time and we don't have access to the geometry of the feature(s) concerned by the transaction during this amount of time. Therefore, we propose the following display rule for transactions: during the first half of the transaction, the geometry of the previous known state is displayed. During the second half of a transaction, the geometry of the following known state is displayed. The type of transaction (creation, modification, etc.) determines the color in which the geometry is displayed. In this example, only creations, modifications and demolitions are managed. However, other transactions could easily be added by following the same rules. Creations are in green, modifications are in yellow and demolitions are in red. Finally, the opacity varies during the time of the transaction in the way that it is equal to 1 at the beginning and at the end of the transaction and to 0 at the half duration of the transaction. Between these timestamps, it decreases on the first half of the transaction (from 1 to 0) and increases during the second half of the transaction (from 0 to 1).

Figure 10 illustrates this proposition on three types of transactions. In this section, we showed a possible use case of the extension we proposed in this paper. Other visualization of the data may be implemented to suit specific user needs since it is independent from the data modelling part. However, this visualization can be useful to understand and share urban evolution which is of big interest for applications such as cultural heritage or urban planning.

Conclusion

Modelling and visualizing the evolution of a city is important for understanding and analyzing urban changes. In this paper, we propose a method for modelling, delivering and visualizing the evolution of cities on the web. First, we proposed a generic conceptual model of standard formats for delivering 3D city models on the web (Gen3DCity). Then, we proposed Gen4DCity, a conceptual model for delivering time-evolving 3D city models, extending

Gen3DCity with a formalization of cities' temporal dimension. Then, we proposed

Logic4DCity, a logical model extending 3D Tiles for time-evolving 3D city models. This step brought us to propose a logical model for 3D Tiles (Logic3DCity). We also proposed a technical specification of the 3D Tiles extension (3DTiles_temporal). These models allow to keep track of the evolution of 3D city models' features at various granularity levels and to add thematic information to these changes. After that, we provided an open source implementation of this extension. This implementation allowed to evaluate the interactivity of the spatio-temporal navigation in large-scale time-evolving 3D city models. In particular, we demonstrated that our contribution allows to significantly improve temporal navigation.

Finally, we proposed rules of visualization for highlighting urban evolution and presented an example of visualization of the city of Lyon, France. These contributions have been made

following the generic approach proposed in section 1 and reproducibility notes are provided to replicate the results.

In the future, mapping of the formalization of the temporal dimension to the I3S standard may be studied in depth. Another lead would be to extend the work on data indexing.

Geospatial web delivery standards allow to organize the data according to spatial indexing methods [START_REF] Azri | Review of Spatial Indexing Techniques for Large Urban Data Management[END_REF]. The temporal extension proposed in this paper makes it possible to use spatio-temporal indexing methods [START_REF] Theodoridis | Specifications for efficient indexing in spatiotemporal databases[END_REF][START_REF] Hadjieleftheriou | Efficient indexing of spatiotemporal objects[END_REF][START_REF] Mokbel | Spatio-temporal access methods[END_REF] or temporal indexing methods (Bertino et al. 2012). It would then be interesting to study the impact of these indexing methods on querying and visualizing 3D tiles with 3DTiles_temporal extension datasets. We for instance expect historical R-Trees [START_REF] Nascimento | Towards historical R-trees[END_REF] to be an efficient indexing method in this case. Finally, this work focuses on the temporal dimension of 3D city models. An interesting lead for the future may be to study an extension of this work to other types of geospatial data supported by geospatial web delivery standard formats.

refer to Articles/2020-IJGIS-Temporal/DatasetVisualization/Readme.md and for section 5.3, refer to Demos/Temporal-LyonMetropole/Readme.md.

Word count: 7003 words.

List of figure captions

List of table titles

Table 1. Comparison of CityGML, 3D Tiles and I3S according to our needs for delivering time-evolving 3D city models on the web. 3D Tiles (DS-3DTiles) and in 3D Tiles extended with 3DTiles_temporal (DS-3DTiles-Tmp).

Table 3. Time for loading and rendering DS-3DTiles and DS-3DTiles-Tmp.

Figure 1 .

 1 Figure 1. Example of the evolution of a building and two possible models based on states modelling and on states and transactions modelling.

Figure 4 presents

 4 Figure4presents Gen4DCity that extends Gen3DCity (in white) with our proposed

Figure 4 .

 4 Figure 4. Gen4DCity: A generic UML conceptual model for delivering time-evolving 3D city models on the web based on 3D Tiles and I3S standards. Entities from Gen3DCity (from Figure 3) appear in white, and entities for temporal information manifest in grey.

Figure 5 .

 5 Figure 5. An example of aggregated transactions.

Figure 6

 6 Figure 6 presents both Logic3DCity and Logic4DCity. Logic3DCity (in white) is a

Figure 6 .

 6 Figure 6. Logic4DCity: UML logical model for time-evolving 3D city models on the web based on extending 3D Tiles. A logical model of 3D Tiles, Logic3DCity, is proposed in white and the temporal extension is represented in gray. The recursive composition association of Feature (thick line) is a conceptual representation of the batch_table_hierarchy extension of 3D Tiles.

  Figure 7 is a proposition of description of these concepts. Extension makes it possible to extend 3D Tiles entities. It has a name and it is composed of an application-specific Object. An Object can be composed of other Objects and/or Attributes. Extensions can be aggregated in an ExtensionSet. An ExtraSet is a collection of Extras. An Extra is an application-specific Attribute, making it possible to add specific metadata to 3D Tiles entities. All the entities of the 3D Tiles specification can have an ExtensionSet and an ExtraSet.

Figure 7 .

 7 Figure 7. Description of the concepts for extending 3D Tiles as a UML conceptual model.

  Tmp represents the buildings of Lyon between 2009 and 2015 but stored as a time-evolving 3D city model in 3D Tiles extended with 3DTiles_temporal. It contains states of buildings along with time-spans and transactions between these states. It has been computed the City Temporal Tiler of py3DTiles (presented in section 5.1). The input data are DS-CityGML and a list of changes between its vintages.

  and 1.4 times smaller than DS-3DTiles. The difference between the CityGML-based representation (DS-CityGML) and the 3D Tiles based representation (DS-3DTiles and DS-3DTiles-Tmp) has two main explanations. First, DS-3DTiles and DS-3DTiles-Tmp do not store the hierarchical structure of the data present in DS-CityGML. It could be added using the batch_table_hierarchy extension of 3D Tiles. Secondly, the representation of the data proposed by 3D Tiles and based on JSON and binary encoding is lighter than the xml-based representation of CityGML. One can also note that while the size of the 2012 vintage of DS-CityGML is higher than the 2015 vintage it is the opposite for DS-3DTiles. This is due to the fact that the 2009 and 2012 vintages of DS-CityGML are stored in CityGML version 1.0 while the 2015 vintage is stored in CityGML version 2.0. However, the version of 3D Tiles is the same for all the vintages of DS-3DTiles. In addition, the 2015 vintage represents buildings at a higher level of detail than the 2009 and 2012 vintages. Therefore, the size of the 2015 vintage is bigger than the size of the 2012 vintage in DS-3DTiles. Comparing the size of DS-3DTiles and DS-3DTiles-Tmp shows one advantage of using the temporal extension proposed in this paper. The model proposed for our extension indeed enables a significant gain in size while allowing the storage of more information describing the evolution of the city (time-spans and transactions between features in this case) in comparison with CityGML and 3D Tiles. The size gain is correlated with the reduction of the number of stored buildings. It indeed falls from 53951 to 36975 between DS-3DTiles and DS-3DTiles-Tmp (which represents a ratio of 1.5). It is explained by the fact that a building having a persistent state in more than one timestamp is stored multiple times in DS-3DTiles but only one time in DS-3DTiles-Tmp. For instance, a building which is in the same state in 2009, 2012 and 2015 is stored three times in DS-CityGML and DS-3DTiles (once in 2009, once in 2012 and once in 2015) and only one time in DS-3DTiles-Tmp (with the time-span

Figure 8

 8 Figure 8 presents a comparison of the animation time when navigating between

Figure 8 .

 8 Figure 8. Animation time comparison of DS-3DTiles and DS-3DTiles-Tmp.

Figure 10 .

 10 Figure 10. Example of visual representation of buildings known states (state i and state i+1) and of transactions between these states. States are in gray, creations in green, modifications in yellow and demolitions in red.

Figure 12 .

 12 Figure 12. Screenshot of the visualization of the city of Lyon in 2014 in UD-Viz, using 3D Tiles extended with 3DTiles_temporal.

Figure 1 .

 1 Figure 1. Example of the evolution of a building and two possible models based on states modelling and on states and transactions modelling.

Figure 2 .

 2 Figure2. Six basic types of transitions between geospatial objects[START_REF] Renolen | Modelling spatiotemporal information: The spatiotemporal object model[END_REF]).

Figure 3 .

 3 Figure 3. Gen3DCity: a generic UML conceptual model for delivering 3D city models on the

Figure 4 .

 4 Figure 4. Gen4DCity: A generic UML conceptual model for delivering time-evolving 3D city

Figure 5 .

 5 Figure 5. An example of aggregated transactions.

Figure 6 .

 6 Figure 6. Logic4DCity: UML logical model for time-evolving 3D city models on the web

Figure 7 .

 7 Figure 7. Description of the concepts for extending 3D Tiles as a UML conceptual model.

Figure 8 .

 8 Figure 8. Animation time comparison of DS-3DTiles and DS-3DTiles-Tmp.

Figure 9 .

 9 Figure 9. Temporal navigation comparison between 3D Tiles and 3D Tiles with temporal

Figure 10 .

 10 Figure 10. Example of visual representation of buildings known states (state i and state i+1)

Figure 11 .

 11 Figure 11. Screenshots showing the evolution of a district of the city of Lyon (in 2013 on the

Figure 12 .

 12 Figure 12. Screenshot of the visualization of the city of Lyon in 2014 in UD-Viz, using 3D

  ). Each Tile has a TileContent that can also have a BoundingVolume, which must closely fit the features of the tile. The TileContent references either a Tileset or a FeatureSet, which is a collection of Features plus some FeatureSetProperty (e.g. number of points, offset, scale, etc.). The

	FeatureSet entity depicts a generalization of the formats proposed by the 3D Tiles community
	to represent features: Batched 3D Model (b3dm), Instanced 3D Model (i3dm), Point Cloud

(pnts) and Composite (cmpt). A Feature (corresponding to Geospatial Feature of Gen3DCity) can have a FeatureGeometry (Geometry of Gen3DCity). It can also have FeatureProperties (Semantic Attribute of Gen3DCity) such as application-specific attributes (e.g. the owner of a building) or appearance information (e.g. color or texture coordinates). A FeatureGeometry can belong to several Features, so it is possible to have a 3D model instanced several times (e.g. with different positions or different scales such as in the i3dm format). At the technical specification level, a FeatureProperty is stored in a batch table or in a feature table

depending

Table 2

 2 compares the size in Megabytes of DS-CityGML, DS-3DTiles and DS-3DTiles-Tmp, as well as the number of buildings they store.

			Size (MB)	Number of buildings
		2009	1100	14827
	DS-CityGML	2012 2015	1100 976	14835 24289
		Total	3176	53951
		2009	182	14827
	DS-3DTiles	2012 2015	183 261	14835 24289
		Total	626	53951
	DS-3DTiles-Tmp	435	36975

Table 2 .

 2 Comparison of a data set representing the buildings of the city of Lyon, France (48 km²) between 2009 and 2015, stored in three different ways: in CityGML (DS-CityGML), in

Table 3

 3 presents the mean time as well as the standard deviation for loading and rendering DS-3DTiles and DS-3DTiles-Tmp, measured on 10 samples. It shows that the time for loading and rendering DS-3DTiles-Tmp is lower than the time for loading and rendering

	all snapshots (2009, 2012 and 2015) of DS-3DTiles. Moreover, DS-3DTiles-Tmp stores
	additional thematic information about the evolution of features in time (transactions and
	features' time-span) in comparison with DS-3DTiles.

Mean loading and rendering time (seconds)

				Standard deviation
				(seconds)
		2009	1.4	0.03
	DS-3DTiles	2012 2015	1.4 1.9	0.04 0.1
		Total	4.7	N.A.
	DS-3DTiles-Tmp	3	0.04
	Table 3. Time for loading and rendering DS-3DTiles and DS-3DTiles-Tmp

Table 2 .

 2 Comparison of a data set representing the buildings of the city of Lyon, France (48 km²) between 2009 and 2015, stored in three different ways: in CityGML (DS-CityGML), in

https://www.opengeospatial.org/standards/wfs

https://www.opengeospatial.org/standards/wms

See extension/3DTILES_batch_table_hierarchy/ folder of the following repository: https://archive.softwareheritage.org/swh:1:rev:50ca4c646da460395b0a06ed85d7f54a727e09a5;orig in=https://github.com/AnalyticalGraphicsInc/3d-tiles/

See definition of time-span page 26 of the current official version (6.2.3) of CIDOC-CRM, accessible here: http://www.cidoc-crm.org/sites/default/files/2018-05-16%23CIDOC%20CRM_v6.2.3_esIP%28XDP%29%28XM%29.pdf

See extension/3DTILES_batch_table_hierarchy/ folder of the following repository: https://archive.softwareheritage.org/swh:1:rev:50ca4c646da460395b0a06ed85d7f54a727e09a5;o rigin=https://github.com/AnalyticalGraphicsInc/3d-tiles/

https://archive.softwareheritage.org/swh:1:dir:2607d3af311abef046958fca57ad2f2f4d929a02;origin= https://github.com/VCityTeam/py3dtiles/

https://archive.softwareheritage.org/swh:1:cnt:189a8695b5e3ea8438499206f88a83e74543ddcd;origin =https://github.com/VCityTeam/py3dtiles/

https://archive.softwareheritage.org/swh:1:rev:14b1e3960962dbb9732d13ec64e583192b452242;origi n=https://github.com/VCityTeam/3DUSE/

https://archive.softwareheritage.org/swh:1:rev:e915ff94f9902fa0def310e159beb3caf461ab59;origin= https://github.com/jailln/UDV/

http://www.itowns-project.org/

https://cesiumjs.org/

https://data.grandlyon.com/

https://archive.softwareheritage.org/swh:1:cnt:489e2b47720e77dc80b5edad89ab175dba30f6ef;origin =https://github.com/VCityTeam/py3dtiles/

Data and codes availability statement

A data model at technical specification level (JSON schemas) is available in figshare.com at https://figshare.com/s/9af2e1f301116ad1247e. A dataset representing the evolution of the first borough of Lyon from 2009 to 2015 using the temporal extension of 3D Tiles presented in this article is available in figshare.com at https://figshare.com/s/f06705add7ea502d276e. Detailed notes for reproducing the results of section 5 are available in the following repository: https://archive.softwareheritage.org/swh:1:rev:96c102a30b2278c5f863f0bc1a5d66122d7d622 d;origin=https://github.com/VCityTeam/UD-Reproducibility/. In particular, for section 5.2.1, refer to Articles/2020-IJGIS-Temporal/DatasetComparison/Readme.md ; for section 5.2.2,

left side and in 2014 on the right side) visualized in UD-Viz and using 3D Tiles extended with 3DTiles_temporal.

In Figure 11, we can clearly identify changes occurring at these two dates. In particular, we can see buildings that are being destroyed (in red), modified (in yellow) and constructed (in green). Figure 12 shows a visualization of the full city of Lyon in 2014.

Visualizing the evolution of the city at this scale can be very useful to detect areas where a lot of changes happen for instance. One can then zoom to these areas to see more details about the changes (such as in Figure 11).


Sylvain Lefort

Dr Véronique Maguer-Satta
email: veronique.maguer-satta@lyon.unicancer.fr

Targeting BMP signaling in the bone marrow microenvironment of Myeloid Leukemia

Keywords: BMP2/4, BMPR1, niche, resistance, persistence, leukemic stem cells, targeted therapies, CML, AML

The BMP pathway regulates the fate and proliferation of normal hematopoietic stem cells (HSC) as well as interactions with their niche. While BMP2 and BMP4 promote HSC differentiation, only BMP4 maintains HSC pool and favors interactions with their niche. In myeloid leukemia, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in Chronic Myeloid Leukemia (CML) and Acute Myeloid leukemia (AML) responsible for leukemic stem cells (LSC) survival. In AML, BMP pathway alterations sustain and promote resistant immature-like leukemic cells by activating a new signaling cascade. Binding of BMP4 to BMPR1A leads to ΔNp73 expression, which in turn induces NANOG, altogether associated with a poor patient's prognosis. Despite efficient targeted therapies, like Tyrosine Kinase Inhibitors (TKI) in CML, many patients retain LSCs. Our laboratory demonstrated that the BMP pathway sustains a permanent pool of LSCs expressing high levels of BMPR1B receptor, that evolve upon treatment to progressively implement a BMP4 autocrine loop, leading to TKIresistant cells. Single cell RNA-Seq analysis of TKI-persisting LSCs showed a co-enrichment of BMP with Jak2-signaling, quiescence and stem cell (SC) signatures. Using a new model of persisting LSCs, we recently demonstrated that BMPR1B+ cells display co-activated Smad1/5/8 and Stat3 pathways and could be targeted by blocking BMPR1B/Jak2 signal.

Lastly, a specific BMPR1B inhibitor impaired BMP4-mediated LSC protection against TKIs.

Altogether, data based on various studies including ours, indicate that BMP targeting could eliminate leukemic cells within protective bone marrow microenvironment to efficiently impact residual resistant or persistent of LSCs in myeloid leukemia.

Cancer is a heterogeneous disease with co-existence of different populations of cancer cells within the same tumor. Some of them have properties that closely resemble normal stem cells (SC), which gave rise to the concept of cancer stem cells (CSCs) [START_REF] Bonnet | Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[END_REF]. Aside from the definition of the origin of the CSC population, the reciprocal influences of tumor cells and their environment appears to be a key element to understand their biology, in order to design more efficient treatments to avoid recurrence [START_REF] Besancon | Cancer stem cells: the emerging challenge of drug targeting[END_REF][START_REF] Maguer-Satta V | The stem cell niche: the black master of cancer[END_REF]. Targeting the dialogue between cancer cells and their niche, by taking advantage of differences in the biology of normal and CSCs, such as differences in surface phenotype, self-renewal/quiescence and stem cell-niche interactions, should allow successful CSC targeting and to improve patient outcome [START_REF] Maguer-Satta V | The stem cell niche: the black master of cancer[END_REF]. Many signaling pathways have consistently been explored, although no major breakthrough has been made.

Among the main pathways that participate in the permanent and dynamic dialogue between the bone marrow microenvironment and resident stem cells, the Bone Morphogenetic Proteins (BMP) signaling constitutes a major bi-directional actor. Indeed, soluble BMP molecules, members of the TGFb superfamily, govern SC regulation during development or in adult tissues including hematopoietic (4), neural and epithelial systems [START_REF] Rendl | BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties[END_REF] both directly and indirectly by affecting their niche [START_REF] Jeanpierre | BMP4 regulation of human megakaryocytic differentiation is involved in thrombopoietin signaling[END_REF][START_REF] Zhang | Identification of the haematopoietic stem cell niche and control of the niche size[END_REF][START_REF] Pickup | TGF-beta, Bone Morphogenetic Protein, and Activin Signaling and the Tumor Microenvironment[END_REF][START_REF] Katagiri | Bone Morphogenetic Proteins[END_REF][START_REF] Clement | Long-term exposure to bisphenol A or benzo(a)pyrene alters the fate of human mammary epithelial stem cells in response to BMP2 and BMP4, by pre-activating BMP signaling[END_REF][START_REF] Chapellier | Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response[END_REF]. Alterations of this pathway have been shown to play a role in cell transformation and progression, in some cases by promoting CSC properties in solid tumors [START_REF] Chapellier | Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response[END_REF][START_REF] Lee | Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells[END_REF][START_REF] Choi | Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2[END_REF] as well as in leukemia [START_REF] Zylbersztejn | The BMP pathway: A unique tool to decode the origin and progression of leukemia[END_REF]. However, most studies have mainly documented events related to advanced stages. BMP ligands control differentiation, angiogenesis, immune response and stromal cell regulation indicating that they could participate in tumor initiation and promote CSC expansion and survival [START_REF] Pickup | TGF-beta, Bone Morphogenetic Protein, and Activin Signaling and the Tumor Microenvironment[END_REF]. One of the main alterations identified affects BMP signaling type 1 serine-threonine receptors responsible for BMP signal transduction through a cascade of protein phosphorylation. Indeed, BMP2 and BMP4 have emerged as key regulators of normal SCs and CSCs, in particular in the hematopoietic system. The importance of the BMP signaling pathway at very early steps of transformation has been evaluated in representative models of CSC in the hematopoietic system including Chronic Myeloid Leukemia-CML (the reference model for SC transformation) and Acute Myeloid Leukemia-AML and breast cancer (representing a solid tumor model containing CSCs, but of debatable origin). In these systems, using primary cells and cellular models of CSCs mimicking early stages of transformation, we revealed major dysregulations of the BMP pathway in SCs and their niche at diagnosis, and showed their direct implication in the emergence and expansion of CSCs. To further test the importance of this pathway to target cancer (leukemic) stem cells (LSCs), the spatio-temporal setting of mechanisms underlying resistance remains to be defined and constitutes a major therapeutic challenge to achieve complete recovery through eradication of persistent LSCs. Here, this review highlights the dynamic alterations of the BMP signaling that occurs during disease progression and which currently remained the most investigated in CML model.

Initiation of BMP signaling alterations in stem cells and their niche

We have demonstrated in CML that transformation of normal hematopoietic SCs (HSCs) by the chromosomal translocation t [START_REF] Katagiri | Bone Morphogenetic Proteins[END_REF][START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF] leading to the expression of the fusion protein BCR-ABL, results in a profound alteration of BMP signaling. These alterations highlight a true dysregulation of this signaling pathway as illustrated by the higher expression of BMPRIB in almost all CML subpopulations at diagnosis at both transcriptional and protein levels. BMPRIB over-expression constitutes an early event in disease progression and is a direct consequence of the introduction of BCR-ABL in immature CD34+ cells (TF1 model) [START_REF] Laperrousaz | Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression[END_REF]. Alterations of the BMP pathway in CML CD34+ cells do not prevent leukemic cells from responding to extracellular stimulation by BMP2/4 but are correlated with the maintenance and amplification of LSCs in response to BMP4. Importantly, BMP4-expanded SCs were all genotypically identified as leukemic cells (Philadelphia Chromosome+, Ph+), suggesting that the biological response of CD34+ cells to BMP2/4 is specifically altered in CML. This contributes to an increased sensitivity of Ph+ cells to external BMP signals [START_REF] Laperrousaz | Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression[END_REF].

While intrinsic genetic alterations are clearly very important, data obtained over the past 15 years argue in favor of a complementary and synergistic role for extrinsic signals that actively participate in the transformation process as well as to promote cancer progression and treatment escape mechanisms [START_REF] Maguer-Satta V | The stem cell niche: the black master of cancer[END_REF][START_REF] Zylbersztejn | The BMP pathway: A unique tool to decode the origin and progression of leukemia[END_REF][START_REF] Gooding | Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease[END_REF]. Remarkably, the donor-induced leukemia constitutes an ultimate proof of that concept. Indeed, in some cases, the allogenic donor remains healthy while the leukemic patient transplanted with cells from this donor develop a new leukemia that results from transformation of these donor-engrafted cells. Moreover, this de-novo leukemia can be similar or different from the initial one that constituted the clinical indication for donor cell transplantation [START_REF] Flynn | Donor cell leukemia: insight into cancer stem cells and the stem cell niche[END_REF]. Therefore, as all hematopoietic cells have been eradicated by radiation during patient conditioning prior to the graft, the only remaining altered signal is likely to come from the patient bone marrow microenvironment itself. More recently, single cell transcriptomic data revealed that BCR-ABL -negative HSC in CML patients are transcriptionally altered when compared to normal donor HSC at the single cell level [START_REF] Giustacchini | Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia[END_REF]. This strengthen how the BM niche changes which occur in leukaemia can influence normal stem cell behavior.

The dynamic and reciprocal dialogue between SCs and their niche is thus of utmost importance for their maintenance and regulation.

In this context, a strong increase in soluble BMP2 and BMP4 levels was measured in the tumoral niche of CML patients [START_REF] Laperrousaz | Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression[END_REF] and was shown to be produced by the SC niche, often dysregulated without being transformed per se [START_REF] Maguer-Satta V | The stem cell niche: the black master of cancer[END_REF]. Indeed, the expression of BMP ligand by leukemic cells was lower [START_REF] Laperrousaz | Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression[END_REF], and, BMP2 for example has been identified as the most repressed gene at the transcriptional level in CML LSCs [START_REF] Gerber | Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations[END_REF]. Surprisingly, similar downregulation of BMP2 has been reported at diagnosis in luminal breast cancer [START_REF] Chapellier | Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response[END_REF], suggesting a common event related to early steps of cell transformation.

At the functional level, these intrinsic and extrinsic alterations of the BMP pathway constitute major events in transformation of immature cells that contribute to sustaining a permanent pool of LSCs and progenitors expressing high levels of the BMPR1B receptor in CML [START_REF] Toofan | Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis[END_REF][START_REF] Laperrousaz | Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression[END_REF][START_REF] Toofan | The role of the bone morphogenetic proteins in leukaemic stem cell persistence[END_REF].

Consistently, a prolonged expression of BCR-ABL in SCs (CML model from TF1 cells) leads to profound changes in DNA replication by changing replication fork features during tumor progression [START_REF] Wu | Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions[END_REF]. These sets of data arising from different studies indicate that, in chronic phase CML, LSCs display a hyper-sensitivity of CD34+ CML cells to soluble BMP ligands abnormally abundant in the bone marrow niche leading to the over amplification of the myeloid compartment, a hallmark of this disease.

BMP signaling is a key pathway to reprogram myeloid leukemic cells in stem-like cells

AML is the first model in which the existence of LSCs was established, leading to the identification of CSCs in numerous hematological malignancies and solid tumors (1). AML is a very complex pathology that displays a large number of distinct genetic alterations linked to the development of this disease, arising in some cases from CML progression. Similarly to what we observed in CML, we have revealed functional alterations of the BMP pathway in AML at diagnosis [START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF]. Conversely to CML for which BMPR1B (Alk6) was identified as the most altered receptor, BMPR1A (Alk3) appears to be the main dysregulated receptor in bone marrow or peripheral blood blast cells isolated from adult AML [START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF]. Furthermore, similarly to CML and breast cancer, higher levels of soluble BMP ligands were also detected, mainly BMP4 for AML [START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF]. Despite the fact that various AML hematopoietic cell lines have been reported to produce BMP4 and BMP2 transcripts [START_REF] Battula | AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth[END_REF], primary AML mononuclear cells showed a decrease in BMP2 and BMP4 transcript [START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF]. However, further investigations are required to determine the origin of high levels of soluble BMP4 protein measured in the bone marrow leukemic niche [START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF]. However, in AMKL, an aggressive form of pediatric AML, appearance of a specific fusion protein CBFA2T3-GLIS2 leads to a drastic overexpression of BMP2 and BMP4, by leukemic cells associated with colony formation capacities, the self-renewal and functional capacities of LSCs [START_REF] Gruber | An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia[END_REF]. This confirms that alterations of the BMP signaling is recurrent in early steps of cancer and also indicates that some specificity related to developmental stage can occur. Further investigations will be required to decipher functional implications of these specificities between adult and pediatric leukemia.

At the functional level, a new signaling cascade linking BMP4 binding to BMPR1A was revealed to imprint immature-like properties to AML blasts through ΔNp73 and NANOG regulation [START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF]. Very interestingly, it was previously reported that murine fibroblasts could be efficiently reprogrammed into myeloid and lymphoid cells through extracellular BMP signaling involving BMP4 [START_REF] Cheng | Reprogramming mouse fibroblasts into engraftable myeloerythroid and lymphoid progenitors[END_REF]. Therefore, such imbalance in BMP4 level may lead to favor an immaturelike phenotype of more mature AML transformed cells [START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF]. These findings imply that alteration of BMP signaling can occur not only in the immature cell compartment but also in more differentiated myeloid cells, enhancing stem-cell features of leukemic cells.

Dynamics of BMP signaling alterations under the pressure of treatment

Numerous studies have focused on the identification of intrinsic hematopoietic cell resistance (or persistence) mechanisms to explain rare primary resistance, though relapse occurs more frequently after an initial hematologic, cytogenetic and even molecular response. In 30-40% of cases, no obvious resistance mechanism to TKI could be identified in CML, including pharmacological ones. During the last decade, consistent demonstrations revealed the critical role of the HSC niche in the development of hematopoietic tumors and their maintenance throughout time [START_REF] Laperrousaz | Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression[END_REF][START_REF] Walkley | A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency[END_REF][START_REF] Raaijmakers | Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia[END_REF][START_REF] Dong | Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment[END_REF][START_REF] Schepers | Activated Gs signaling in osteoblastic cells alters the hematopoietic stem cell niche in mice[END_REF][START_REF] Krause | Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells[END_REF][START_REF] Zhang | Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia[END_REF][START_REF] Lopez | Mesenchymal stromal cells derived from the bone marrow of acute lymphoblastic leukemia patients show altered BMP4 production: correlations with the course of disease[END_REF]. Although the microenvironment is dissimilar in different tumors, involving multiple cell types and proteins, it may exert and pervert tumor cells and favor their resistance to treatments. This phenomenon is emerging as a new paradigm to explain resistance of solid tumors [START_REF] Krause | A hostel for the hostile: the bone marrow niche in hematologic neoplasms[END_REF].

A growing body of evidence suggests that molecular and functional alterations evolve upon treatment. Based on recent technological breakthroughs, several SCs subpopulations have been identified in CML, with distinct and dynamic proportions at diagnosis and following TKI treatment [START_REF] Giustacchini | Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia[END_REF][START_REF] Warfvinge | Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML[END_REF]. This raised the hypothesis that resistance could emerge from the heterogeneity of LSC subpopulations depending on the cues delivered by their microenvironment. As several studies have demonstrated that BMP pathway alterations play a fundamental and recurrent role in early stages of SC transformation [START_REF] Toofan | Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis[END_REF][START_REF] Zylbersztejn | The BMP pathway: A unique tool to decode the origin and progression of leukemia[END_REF][START_REF] Laperrousaz | Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression[END_REF][START_REF] Toofan | The role of the bone morphogenetic proteins in leukaemic stem cell persistence[END_REF][START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF][START_REF] Gruber | An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia[END_REF], this suggests that this signaling is most likely to be involved in resistance of leukemic cells and especially of LSCs. This concept was formally established by analyzing bone marrow samples of LSCs and progenitors isolated from patients either sensitive or resistant to TKI, which showed that several elements of the BMP and TGF signaling pathways remained highly modified or evolved upon treatment and were correlated with LSC survival [START_REF] Naka | TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia[END_REF][START_REF] Toofan | Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal[END_REF][START_REF] Grockowiak | Immature CML cells implement a BMP autocrine loop to escape TKI treatment[END_REF]. In CML resistant cells, a specific molecular signature based on dysregulated genes from the TGF and BMP signaling in mature and immature cells was correlated with a poor response to TKI treatment [START_REF] Toofan | Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal[END_REF]. Earlier studies have identified in both primary cells and CML cell lines the abnormal expression of the embryonic transcription factor Twist-1 as an actor of CML TKIresistance, especially in LSCs [START_REF] Cosset | Deregulation of TWIST-1 in the CD34+ compartment represents a novel prognostic factor in chronic myeloid leukemia[END_REF][START_REF] Tipping | Comparative gene expression profile of chronic myeloid leukemia cells innately resistant to imatinib mesylate[END_REF]. It is now established that LSCs adapt to targeted therapy by implementing a BMP4 autocrine loop simultaneously to a sustained and increased dysregulation of the LSC niche upon long-term treatment [START_REF] Grockowiak | Immature CML cells implement a BMP autocrine loop to escape TKI treatment[END_REF]. This leads to a further increase in BMPR1B expression that upon BMP4 signal induces the upregulation of Twist-1 expression, altogether protecting LSCs from TKI-driven cell death [START_REF] Grockowiak | Immature CML cells implement a BMP autocrine loop to escape TKI treatment[END_REF].

Most AML patients achieve complete remission after intensive induction chemotherapy, but the majority of them relapse within several years. Recurrence may reflect the survival of resistant immature-like LSCs after chemotherapy [START_REF] Shlush | Tracing the origins of relapse in acute myeloid leukaemia to stem cells[END_REF]. In AML leukemic cells, a signaling cascade involving BMP4 binding to BMPR1A drive ΔNp73 and NANOG expression to sustained an immature-like phenotype. It also identified potential markers to predict relapse of AML patients at diagnosis and explained survival and features of immature bone marrow AML cells [START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF]. A previous study highlighted the importance of the BMP pathway in adult AML, using various cell lines [START_REF] Raymond | A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy[END_REF]. Interestingly, BMP4 controls the expression of the MIXL1 gene, aberrantly expressed in AML and involved in early steps of leukemogenesis in a mouse model [START_REF] Glaser | Enforced expression of the homeobox gene Mixl1 impairs hematopoietic differentiation and results in acute myeloid leukemia[END_REF]. The predictive value of BMPR1 and downstream targets suggests that targeting the BMP pathway could be of interest in adult AML. Indeed, BMP type-1 receptors inhibition has been shown to efficiently impact MIXL1-expressing AML cells [START_REF] Raymond | A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy[END_REF]. Collectively, these data support that targeting the BMP pathway could constitute a new therapeutic tool to decrease the progenitor capacity of LSCs [START_REF] Gruber | An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia[END_REF][START_REF] Busch | Bone marrow niche crosses paths with BMPs: a road to protection and persistence in CML[END_REF].

Multi-targeting of BMP signaling impairs persistent LSC survival in their leukemic ecosystem

Eradication of LSCs then raises many hopes in the treatment of cancer but remains a challenge justifying the importance for better understanding the mechanisms underlying LSC persistence and survival under treatment. Recent CML single-cell level analysis revealed the selective persistence of a distinct and highly quiescent CML LSC subset already present at diagnosis [START_REF] Giustacchini | Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia[END_REF]. Indeed, in chronic phase, regardless of patient response to TKI, a fraction of CML LSCs survive, sustained by interactions with their niche responsible for disease persistence and relapse following treatment cessation due to the implementation of resistance mechanisms [START_REF] Bhardwaj | Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation[END_REF][START_REF] Fuchs | Inhibition of Smad5 in human hematopoietic progenitors blocks erythroid differentiation induced by BMP4[END_REF]. We have recently investigated downstream signaling involved in LSC persistence in patients under TKI treatment and identified a sub-fraction of LSCs that specifically co-activate the BMP/BMPR1B and Jak2/Stat3 signaling in bone marrow of CML patients in remission following treatment. Using a model of persisting LSCs, the importance of the BMP signaling in SC dormancy driven by its tumor microenvironment was identified as responsible for disease persistence in response as an adaptation to treatment [START_REF] Jeanpierre | The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission[END_REF]. When CML CD34 + -cells persist under continuous TKI-treatment, all BMPR1B+ cells co-activate Smad1/5/8 and Stat3 pathways. These cells could then be efficiently targeted by blocking BMPR1B/Jak2 signaling using the BMPR-1B inhibitor (E6201) that triggers LSC death, and/or the JAK2/STAT3 inhibitor (AG490) [START_REF] Jeanpierre | The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission[END_REF]. The importance of the JAK2 and Stat3 signaling in CML LSC persistence was previously reported by several groups [START_REF] Chakraborty | Combination of JAK2 and HSP90 inhibitors: an effective therapeutic option in drug-resistant chronic myelogenous leukemia[END_REF][START_REF] Eiring | STAT3 as a mediator of BCR-ABL1-independent resistance in chronic myeloid leukemia[END_REF][START_REF] Eiring | Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia[END_REF][START_REF] Kuepper | Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling[END_REF]. This underlines the importance of synergistic effects between BMP and Jak2 targeting in order to eradicate LSCs that persist in the tumor microenvironment, even in patients with apparent good treatment response [START_REF] Jeanpierre | The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission[END_REF]. In the context of resistant CML cells, dual targeting using TKI and BMP inhibition efficiently reduce the number of LSCs and derived progenitors [START_REF] Toofan | Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal[END_REF]. This indicates that BMP-specific inhibitors could be efficient at different stages of disease progression including advanced CML that could transform into AML as previously discussed [START_REF] Raymond | A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy[END_REF]. However, we have unveiled that only BMPR1B-expressing cells that closely interact with stromal cells of the leukemic niche enter quiescence in the presence of TKI treatment.

Impairing the BMP4 survival signal provided by this niche releases LSCs from quiescence and allows them to enter differentiation. Importantly, the BMPR inhibitor alone is capable of simultaneously blocking BMP production by stromal cells surrounding LSCs while other current treatments by themselves are inefficient in doing so. In addition, in AML, soluble BMPs induce Smad1/5 signaling in the bone marrow stromal cells to control their osteogenic differentiation suggesting that targeting of the BMP signaling could not only target leukemic cells [START_REF] Raymond | A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy[END_REF] but also could contribute to restore normal MSC differentiation [START_REF] Battula | AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth[END_REF]. Indeed, the monitoring of patients under TKI treatment for almost a decade has clearly highlighted that alteration of the leukemic niche in CML is not corrected by current treatments in either resistant [START_REF] Grockowiak | Immature CML cells implement a BMP autocrine loop to escape TKI treatment[END_REF] or sensitive CML patients [START_REF] Jeanpierre | The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission[END_REF].

Conclusion

The current paradigm of leukemogenesis implies a multistep process that involves different types of genetic alterations with no obvious hierarchy and understanding of the sequential clonal selection [START_REF] Hirsch | Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia[END_REF]. In this context, crosstalk between LSCs and the associated bone marrow stroma appears as an essential relationship for leukemic progression, and response to therapy [START_REF] Zhou | Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang[END_REF][START_REF] Shafat | Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment[END_REF]. Moreover, crosstalk between BMP signaling (either canonical/Smad dependent or non-canonical/Smad independent) with other pathways emerge as an important parameter to decipher how BMP-signaling constitute a complex and dynamic molecular platform at the interplay between hematopoietic cells and their surrounding microenvironment during leukemia progression [START_REF] Sharma | Ally to adversary: mesenchymal stem cells and their transformation in leukaemia[END_REF]. Following long-term continuous targeted therapy, LSCs adapt and escape through diverse mechanisms. BMP signaling is then likely to constitute a recurrent way for LSCs to persist and escape drug pressure while allowing them to foster slow disease progression. Both the progressive implementation of an intrinsic BMP autocrine loop and the permanent exogenous and continuous increase in dysregulations of BMP ligand production by the LSC microenvironment thus favor the continuous evolution and progress of CML into an accelerated phase in some cases leading to AML transformation. Therefore, despite relative efficient therapies, many patients suffering from myeloid leukemia retain persistent LSCs and would then benefit from their eradication within the remission period achieved by current therapies. To that aim, the BMP pathway appears to be an emerging important target constituting a regulator to sustain a permanent pool of LSCs expressing high levels of the type 1 BMP receptor, that evolve upon treatment to further dysregulate resistant cells. Therefore, targeting both BMPR1 and the protective bone marrow microenvironment that provides BMP ligands could efficiently impact residual resistant or persistent LSCs at different stages of myeloid progression (Figure 1).

Altogether, several studies have demonstrated in various cancers that CSCs display a hypersensitivity to BMP signals that contribute to setting the tumor ecosystem and promoting dynamic remodeling. This pathway represents a very early and efficient target for the development of new therapeutic strategies. Importantly, in both myeloid leukemia [START_REF] Laperrousaz | Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression[END_REF][START_REF] Voeltzel | A new signaling cascade linking BMP4, BMPR1A, DeltaNp73 and NANOG impacts on stem-like human cell properties and patient outcome[END_REF] and breast cancers [START_REF] Chapellier | Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response[END_REF], we highlighted the important functions of the BMP receptor type 1, since its activation results in the amplification of a normal response to BMP in SCs and contributes to the survival of CSCs independently of the initial transforming event. Due to the broad involvement of BMP signaling in cancer, identification of recurrent alterations of this pathway is becoming an important common feature in different cancers. Indeed, it is increasingly evident that, in addition to their known role at late stages of the disease, BMP pathway alterations play a fundamental and recurrent role at early stages of SC, in their expansion and maintenance, treatment escape and tumor progression. Thus increasing evidence identifies this signaling pathway as a robust target to either eradicate LSCs early on or prevent their further progression.

Perspectives

(i) The adult bone marrow provides essential niches for hematopoietic stem cell (HSC) maintenance and differentiation to meet the demand of blood and immune cell production during homeostasis and stress.

(ii) The BMP pathway regulates the fate and proliferation of normal stromal and HSC and modulates their permanent dialogue. It is also an essential actor of leukemic stem cells (LSC) persistence and niche remodeling in Chronic Myeloid Leukemia (CML) and Acute Myeloid leukemia (AML).

(iii) As the BMP pathway is involved in regulating LSC and their niche from early stages of the disease to tumor escape and resistance to treatments, patients would benefit from specific targeting of the BMP signaling to achieve persistent LSC eradication and restore a normal bone marrow microenvironment.

Figure 1 :

 1 Figure 1: Evolution of BMP signaling alterations in the tumor ecosystem of CML, from

Funding and Acknowledgements

We thank P. Battiston (Cytometry Facility, CRCL, Lyon) for her technical assistance, B.

Manship for English editing. We thank Dr T. Myers from Spirita Oncology for providing us with E6201. Fundings from: patients' association LMC France and her president Mrs Mina Daban; "Fondation de France" 2014-0047501 and 2017-00076282/Fondation Ramona Ehrman Amador, "Association Laurette Fugain" ALF2014-03, Ligue contre le Cancer (Haute Savoie, Loire, Puy de Dôme and Rhone), "Association ALTE-SMP", the Institut Convergence PLASCAN grants to V.M-S; S.L. and/or F-E.N. PhD fellowship was obtained from "Ligue contre le cancer" (K.A).