Michel Arock
email: michel.arock@aphp.fr

Karl Sotlar

Jason Gotlib

Wolfgang R Sperr

Karin Hartmann

Lawrence B Schwartz

Cem Akin

Hans-Peter Horny

Peter Valent

New developments in the field of mastocytosis and mast cell activation syndromes: a summary of the Annual Meeting of the European Competence Network on Mastocytosis (ECNM) 2019

Keywords: Mast cell activation, mastocytosis, KIT, classification, scoring, tyrosine-kinase inhibitors Leuk Lymphoma

Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical mast cells in one or several organs/tissues, often accompanied by mast cell activation. Whereas in children the disease manifestations are mostly limited to the skin, in adults the disease is usually systemic (systemic mastocytosis; SM) and involves the bone marrow and/or other internal organs. Several variants of SM have been defined. Whereas most patients have indolent SM, some patients have advanced SM, which underlines the complexity of SM. In 2002, a European consortium of clinicians and scientists initiated a multidisciplinary, multi-national cooperative network, termed the 'European Competence Network on Mastocytosis' (ECNM), with the aim to improve diagnosis and therapy of patients with mastocytosis and other mast cell activation disorders. Since then, members of the ECNM have organized Annual Meetings in several European countries. The present article provides a summary of advances in the field presented during the 17th Annual ECNM meeting held in Salzburg in October 2019.

Introduction

Mastocytosis is a term used to denote a heterogeneous group of diseases characterized by abnormal accumulation of mast cells (MCs) in one or more organs. Depending on the organ(s) and/or tissue(s) involved, mastocytosis is divided into cutaneous mastocytosis (CM), systemic mastocytosis (SM), and, rarely, localized MC tumors. Based on the 2016 classification of the World Health Organization (WHO), several variants of CM and SM have been defined (Table 1) [START_REF] Valent | Advances in the classification and treatment of mastocytosis: current status and outlook toward the future[END_REF][START_REF] Valent | Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts[END_REF]. The prognosis and symptoms vary among patients depending on the disease variant, the presence of an additional hematologic neoplasm (AHN) as well as the presence of comorbidities [START_REF] Valent | Advances in the classification and treatment of mastocytosis: current status and outlook toward the future[END_REF][START_REF] Valent | Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts[END_REF]. Independent of the variant of CM or SM, patients may suffer from mediator-related symptoms which can range from moderate to severe, or even life-threatening [START_REF] Valent | Mastocytosis: a paradigmatic example of a rare disease with complex biology and pathology[END_REF]. In some of these cases, a MC activation syndrome (MCAS) is diagnosed [START_REF] Valent | Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome[END_REF]. Advanced SM can further be divided into WHO-approved variants, including aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and MC leukemia (MCL) [START_REF] Ustun | Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice[END_REF]. In these patients, MC infiltration leads to organ damage, which can manifest as cytopenia, ascites, malabsorption, lymphadenopathy, splenomegaly (hypersplenism), hepatomegaly (impaired function), or large osteolyses with pathologic fractures [START_REF] Ustun | Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice[END_REF]. Whereas the prognosis in CM and indolent SM (ISM) is excellent, the prognosis in patients with advanced SM is poor [START_REF] Pardanani | Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management[END_REF].

In 2002, European experts working in the field of mastocytosis established a Competence Network in Europe [START_REF] Valent | The European Competence Network on Mastocytosis (ECNM)[END_REF][START_REF] Valent | European Competence Network on Mastocytosis (ECNM): 10year jubilee, update, and future perspectives[END_REF]. This network, termed the 'European Competence Network on Mastocytosis' (ECNM), was initiated as a multidisciplinary, multi-national cooperative approach to increase awareness and to improve the diagnosis and therapy of mastocytosis [START_REF] Valent | The European Competence Network on Mastocytosis (ECNM)[END_REF][START_REF] Valent | European Competence Network on Mastocytosis (ECNM): 10year jubilee, update, and future perspectives[END_REF]. The network is composed of local centers, physicians and scientists who dedicate specifically their work to patients with mastocytosis [START_REF] Valent | The European Competence Network on Mastocytosis (ECNM)[END_REF][START_REF] Valent | European Competence Network on Mastocytosis (ECNM): 10year jubilee, update, and future perspectives[END_REF]. Representatives of the ECNM cooperate closely with their US colleagues, with patient-organizations in Europe and in the USA, and with other scientific networks [START_REF] Valent | The European Competence Network on Mastocytosis (ECNM)[END_REF][START_REF] Valent | European Competence Network on Mastocytosis (ECNM): 10year jubilee, update, and future perspectives[END_REF]. In 2012, the ECNM launched a mastocytosis registry [START_REF] Valent | The data registry of the European Competence Network on Mastocytosis (ECNM): set up, projects, and perspectives[END_REF]. As of September 2019, more than 3800 patients were included in this registry. Using the central database of this registry, cooperative multicenter studies have been conducted and several manuscripts arising from these studies have been published or submitted for publication, or are currently being prepared [START_REF] Valent | The data registry of the European Competence Network on Mastocytosis (ECNM): set up, projects, and perspectives[END_REF].

Members of the ECNM also organize Annual Meetings of the ECNM in Europe. In 2019, the Annual ECNM meeting took place in Salzburg (Austria) from the 3rd to the 5th of October, 2019. At this meeting, experts from various European countries and from the US presented their center-related activities and data on various projects, including those based on data from the ECNM registry. The current article summarizes advances in the science and the clinical diagnosis, prognosis, and treatment of primary MC disorders presented at the 2019 ECNM meeting. In addition, we provide an overview of ongoing activities and new concepts arising within the ECNM.

Highlights in basic and translational research on mast cell diseases

During the Annual ECNM meeting, several groups presented new and emerging concepts in basic and translational science. As pointed out by the coordinator of the ECNM, Peter Valent, and the chair of the ECNM, Michel Arock, the ECNM plans to establish a strong basic science network in Europe that is connected with the Centers of Excellence and with Reference centers of the ECNM, and is also linked to a strong biobank system and to the ECNM registry database. In addition, the basic science section of the ECNM should promote translational research in various centers and supports ECNM-wide efforts to facilitate applications for EU grants and other multi-center grants. In Austria, the Ludwig Boltzmann Institute for Hematology and Oncology (LBI HO), headed by Peter Valent, has dedicated one project line to basic and translational research on mastocytosis [START_REF] Valent | Ludwig Boltzmann Cluster Oncology (LBC ONC): first 10 years and future perspectives[END_REF]. For example, in collaboration with the Mannheim center of excellence and the CEREMAST center of excellence in Paris, the LBI HO has recently identified NSG SCF -repopulating neoplastic stem cells in advanced SM, including MCL [START_REF] Eisenwort | Identification of a leukemia-initiating stem cell in human mast cell leukemia[END_REF]. The same collaborative group has also recently demonstrated that CD44 is a RAS/MEK/STAT5-dependent adhesion molecule expressed on neoplastic MCs and that levels of CD44 on MCs and neoplastic stem cells increase with disease aggressiveness [START_REF] Mueller | CD44 is a RAS/STAT5-regulated invasion receptor that triggers disease expansion in advanced mastocytosis[END_REF]. Another project, presented by Martin Zenke in Salzburg, described the generation of SM-related neoplastic MCs from patient-derived inducible pluripotent stem cells (iPSC). Other presentations discussed the cellular and molecular mechanisms of mast cell activation (MCA) and the mechanisms underlying clinical symptoms in patients with mast cell activation syndromes (MCAS). In addition, the mechanisms contributing to clinical symptoms in patients with hereditary alpha-tryptasemia (HAT) were discussed [START_REF] Sabato | Familial hypertryptasemia with associated mast cell activation syndrome[END_REF][START_REF] Lyons | Hereditary alpha tryptasemia: genotyping and associated clinical features[END_REF]. Lawrence Schwartz presented data on α/β-tryptase heterotetramers in the context of HAT [START_REF] Sabato | Familial hypertryptasemia with associated mast cell activation syndrome[END_REF][START_REF] Lyons | Hereditary alpha tryptasemia: genotyping and associated clinical features[END_REF]. In particular, hetero-tetramers composed of 2α-and 2β-tryptase protomers (α/β-tryptase) form naturally in individuals who express α-tryptase. α/β-tryptasehetero-tetramers, but not homotetramers, activate protease-activated receptor-2 (PAR2), a multifunctional receptor expressed on smooth muscle, neurons, and endothelial cells [START_REF] Le | Impact of naturally forming human alpha/beta-tryptase heterotetramers in the pathogenesis of hereditary alpha-tryptasemia[END_REF].

There is also an increasing interest of industrial partners and academic networks to collaborate with centers and groups of the ECNM. For example, representative of several companies working on the development of novel KIT-targeting drugs attended the 2019 ECNM meeting. In addition, several representatives of the European Mast Cell and Basophil Research Network (EMBRN) (a basophil/mast cell network in Europe) joined in this annual meeting of the ECNM.

Studies on mast cell activation (MCA) and mast cell activation syndromes (MCAS)

MCA can be documented in a number of physiologic and pathologic conditions [START_REF] Valent | Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome[END_REF][START_REF] Akin | Mast cell activation syndrome: proposed diagnostic criteria[END_REF][START_REF] Valent | Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal[END_REF][START_REF] Valent | Mast cell activation syndromes: definition and classification[END_REF][START_REF] Theoharides | Mast cells, mastocytosis, and related disorders[END_REF][START_REF] Weiler | AAAAI Mast Cell Disorders Committee Work Group Report: mast cell activation syndrome (MCAS) diagnosis and management[END_REF]. Acute MCA, secondary to allergen exposure, is thus encountered in IgE-mediated allergic reactions and, when severe, may result in systemic anaphylaxis. Severe or even lifethreatening MCA may be facilitated when (1) the burden of MCs is high (although anaphylactic reactions are also seen in cases with low MC counts), [START_REF] Valent | Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts[END_REF] when MCs are in a hyperactivable state, and (3) when comorbidities make the patient less tolerant to MCA events [START_REF] Valent | Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome[END_REF][START_REF] Akin | Mast cell activation syndrome: proposed diagnostic criteria[END_REF][START_REF] Valent | Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal[END_REF][START_REF] Valent | Mast cell activation syndromes: definition and classification[END_REF][START_REF] Theoharides | Mast cells, mastocytosis, and related disorders[END_REF]. When MC involvement is documented and the reaction is severe, an MCA syndrome (MCAS) may be diagnosed [START_REF] Valent | Mast cell activation syndromes: definition and classification[END_REF]. Based on the recommendations of the EU/US consensus group [START_REF] Valent | Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome[END_REF][START_REF] Akin | Mast cell activation syndrome: proposed diagnostic criteria[END_REF][START_REF] Valent | Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal[END_REF][START_REF] Valent | Mast cell activation syndromes: definition and classification[END_REF], MCAS is diagnosed when the following criteria apply: (i) documented recurrent episodes of typical systemic symptoms that are produced by MC mediators and involve at least 2 organ systems, (ii) an event-related transient elevation of the serum tryptase level by at least 20% over the individual baseline plus 2 ng/mL within a 1-4 h after onset of the reaction, and (iii) a documented clinically meaningful response to drugs that either target MC-derived mediators (e.g. H1 antihistamines) and/or suppress MC activation (e.g. omalizumab) (Table 2) [START_REF] Valent | Mast cell activation syndromes: definition and classification[END_REF]. With regard to tryptase, it was stressed repeatedly during the meeting that an elevated basal serum tryptase level in itself is not a sufficient criterion to define MCA, as elevated basal serum tryptase levels can be found transiently or permanently during a number of conditions, including anaphylaxis, hereditary alpha-tryptasemia, mastocytosis (CM and SM), myelodysplastic syndromes, myeloproliferative neoplasms, chronic eosinophilic leukemia, chronic and acute myeloid leukemias, chronic helminth infection and chronic renal failure [START_REF] Lyons | Hereditary alpha tryptasemia: genotyping and associated clinical features[END_REF][START_REF] Valent | Why the 20% + 2 tryptase formula is a diagnostic gold standard for severe systemic mast cell activation and mast cell activation syndrome[END_REF]. It is also important to know that based on its etiology, MCAS can be classified using criteria proposed by the consensus group (Table 3) [START_REF] Valent | Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome[END_REF][START_REF] Akin | Mast cell activation syndrome: proposed diagnostic criteria[END_REF][START_REF] Valent | Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal[END_REF][START_REF] Valent | Mast cell activation syndromes: definition and classification[END_REF]. Thus, MCAS can be divided into (i) primary (clonal (also known as monoclonal MCAS; MMAS), e.g. KIT with Gain of Function (KIT GOF ) mutation, or genetic, e.g. hereditary alpha-tryptasemia)) MCAS, (ii) secondary MCA, where an allergic or other triggers of MC activation are involved, and (iii) idiopathic MCAS, presumably primary, but where neither a clonal, genetic or known agonist of MCs is found (Table 3). There are also reports suggesting the HAT can predispose to MC activation [START_REF] Le | Impact of naturally forming human alpha/beta-tryptase heterotetramers in the pathogenesis of hereditary alpha-tryptasemia[END_REF]. In addition, more genetic or clonal disorders associated with idiopathic MCAS may be identified in the near future. However, not all MC activation events meet criteria of MCAS. Therefore, it is important to apply and follow criteria for MCAS since more and more patients are misdiagnosed as having MCA/MCAS without having completed a thorough and appropriate medical/biological examination. To prevent misdiagnoses, a diagnostic algorithm has been proposed (Figure 1) through which a clinically relevant (systemic) MCA can be suspected and MCAS can subsequently be documented or excluded [START_REF] Valent | Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome[END_REF]. This algorithm should help guide care providers to consider the principal diagnoses that may underlie systemic MCA events, namely, severe allergy, SM and HAT [START_REF] Valent | Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome[END_REF].

Updated prognostication tools for mastocytosis

The 2016 WHO classification of mastocytosis (Table 1) plays a pivotal role in the stratification of patients and is thus a most important initial prognostication tool [START_REF] Valent | Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts[END_REF]. However, this classification alone is not sufficient to estimate the risk of progression in individual patients with SM. For instance, although patients with ISM have in general an excellent prognosis, some of these patients may finally progress to SM-AHN, ASM or MCL [START_REF] Lim | Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors[END_REF][START_REF] Escribano | Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients[END_REF]. During the past few years a number of prognostic variables predicting progression of ISM/SSM to a high-grade disease have been identified, including multi-lineage involvement of hematopoietic cells with KIT D816V, the variant allele frequency (VAF) of mutated KIT, lymphadenopathy, splenomegaly, and an elevated β2-microglobulin or alkaline phosphatase level [START_REF] Teodosio | An immature immunophenotype of bone marrow mast cells predicts for multilineage D816V KIT mutation in systemic mastocytosis[END_REF][START_REF] Erben | The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis[END_REF][START_REF] Jawhar | Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis[END_REF][START_REF] Greiner | Molecular quantification of tissue disease burden is a new biomarker and independent predictor of survival in mastocytosis[END_REF]. However, there is still a need to establish robust and reliable prognostic scoring systems that predict: (1) the risk of progression of ISM patients into more aggressive variants of the disease, and (2) the overall survival and progression-free survival of those with advanced SM. Recently, two multi-parametric risk models have been established, leading to two similar scoring systems, both based on age, hemoglobin level, platelets count and alkaline phosphatase level: the clinical risk model (CRM) established at the Mayo Clinic on 277 patients, but not further validated [START_REF] Pardanani | Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models[END_REF], and the clinical risk score (CRS), presented at the ECNM 2019 meeting, based upon a German training cohort of 197 patients that was validated in a group of 149 additional patients [START_REF] Jawhar | MARS: Mutation-Adjusted Risk Score for advanced systemic mastocytosis[END_REF].

A novel improved prognostic scoring system was also presented at the 2019 ECNM meeting: the International Prognostic Scoring System for Mastocytosis (IPSM) [START_REF] Sperr | International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study[END_REF]. The IPSM was established by analyzing the prognostic relevance of clinical and laboratory parameters in 1794 mastocytosis patients collected in the ECNM registry [START_REF] Sperr | International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study[END_REF]. For validation, 462 patients from the Spanish mastocytosis-network were examined. In this study, the prognostic value of the WHO classification was confirmed. However, the data generated in this study also demonstrates that in 1533 patients with non-advanced mastocytosis, two parameters, namely age ≥60 years and alkaline phosphatase ≥100 U/L, are additional independent prognostic variables for survival [START_REF] Sperr | International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study[END_REF]. Thus, this new scoring system (IPSM) divides patients with non-advanced mastocytosis into 3 groups: low risk (no risk factors), intermediate risk (one risk factor), and high risk (both risk factors) [START_REF] Sperr | International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study[END_REF]. Interestingly, overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) differed significantly among these subgroups and between these subgroups and advanced SM [START_REF] Sperr | International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study[END_REF]. Besides, in 261 patients with advanced SM, age ≥60 years (1 point), tryptase ≥125 ng/ml (1 point), leukocytes ≥16 x 10 9 /L (1 point), hemoglobin ≤11 g/dL (1 point), platelets ≤100 x 10 9 /L (1 point) and skin involvement (-1 point) were found to be of prognostic value, leading to the establishment of a separate score for advanced SM, which delineates 4 risk groups (AdvSM-1: -1 to 0 point; AdvSM-2: 1 point; AdvSM-3: 2-3 points and AdvSM-4: 4-5 points) of prognostic significance for OS, PFS and EFS. The value of both scores was confirmed in the Spanish validation-cohort [START_REF] Sperr | International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study[END_REF]. The IPSM utilizes thus routinely applicable prognostic parameters for non-advanced mastocytosis (age and alkaline phosphatase) and for advanced SM (age, tryptase, blood counts and skin involvement), allowing to reach a robust prognostication score useful in daily clinical practice.

However, the IPSM does not take into account molecular defects frequently encountered in patients with advanced SM. Particularly in patients with SMAHN, additional molecular mutations, apart from KIT D816V, have been described and found to be of major prognostic significance [START_REF] Jawhar | Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis[END_REF][START_REF] Traina | Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis[END_REF][START_REF] Hanssens | SRSF2-p95 hotspot mutation is highly associated with advanced forms of mastocytosis and mutations in epigenetic regulator genes[END_REF][START_REF] Schwaab | Comprehensive mutational profiling in advanced systemic mastocytosis[END_REF][START_REF] Jawhar | The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm[END_REF]. Thus the mutationadjusted risk score (MARS) for advanced SM was developed with the intention to integrate clinical and mutation characteristics in the scoring system which was discussed in Salzburg [START_REF] Jawhar | MARS: Mutation-Adjusted Risk Score for advanced systemic mastocytosis[END_REF]. The MARS study included 383 patients with advanced SM from the German Registry on Disorders of Eosinophils and Mast Cells (training set; n = 231) and several centers for mastocytosis in the United States and Europe (validation set; n = 152) [START_REF] Jawhar | MARS: Mutation-Adjusted Risk Score for advanced systemic mastocytosis[END_REF]. The following risk factors were identified concerning overall survival (OS) in multivariate analyses: age >60 years (1 point), anemia (hemoglobin <10 g/dL) (1 point), thrombocytopenia (platelets <100 x 10 9 /L) (1 point), presence of one high risk gene mutation (1 point) and presence of two or more high risk gene mutations in the SRSF2/ASXL1/RUNX1 (S/A/R) panel (2 points) (Table 4) [START_REF] Jawhar | MARS: Mutation-Adjusted Risk Score for advanced systemic mastocytosis[END_REF]. By assigning hazard ratio-weighted points to these variables, the following three risk categories were defined: low risk (0 to 1 point), intermediate risk (2 points), and high risk (3 to 5 points). The MARS was independent of the WHO classification and was confirmed in an independent validation set [START_REF] Jawhar | MARS: Mutation-Adjusted Risk Score for advanced systemic mastocytosis[END_REF]. In conclusion, the MARS is a validated, five-parameter, WHO-independent prognostic score that defines three risk groups among patients with advanced SM. However, the therapeutic/treatment implication of the various risk scores remains an open question and the implementation of the scores in prospective studies is needed.

Highlights on new therapeutic concepts in mastocytosis

ISM therapy is mainly focused on symptom relief and based on histamine 1 receptor (H1R) and H2R blockers and on MC-stabilizing agents [START_REF] Valent | Advances in the classification and treatment of mastocytosis: current status and outlook toward the future[END_REF][START_REF] Valent | Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts[END_REF]. More recently the leukotriene receptor antagonist montelukast, which acts by blocking action of MC-derived leukotrienes, and the humanized monoclonal antibody directed against IgE, omalizumab (Xolair ® ), which inhibits MC activation, have been introduced for the treatment of severe mediator-related symptoms in mastocytosis [START_REF] Tolar | Leukotriene-receptor inhibition for the treatment of systemic mastocytosis[END_REF][START_REF] Broesby-Olsen | Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: efficacy and safety observations[END_REF][START_REF] Lemal | Omalizumab therapy for mast cell-mediator symptoms in patients with ISM, CM, MMAS, and MCAS[END_REF]. Some of the cytoreductive agents, like cladribine, are also known to reduce mediator-related symptoms by reducing the MC burden and by directly blocking MC activation in patients with SM [START_REF] Kluin-Nelemans | Cladribine therapy for systemic mastocytosis[END_REF][START_REF] Bohm | In vitro and in vivo growth-inhibitory effects of cladribine on neoplastic mast cells exhibiting the imatinib-resistant KIT mutation D816V[END_REF][START_REF] Barete | Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis[END_REF]. However, these cytoreductive drugs also have (sometimes severe) side effects and therefore usually are avoided in ISM patients who respond to less intensive therapies [START_REF] Barete | Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis[END_REF][START_REF] Akin | Cladribine for mastocytosis: benefits and risks[END_REF][START_REF] Alstadhaug | Progressive multifocal leukoencephalopathy in a patient with systemic mastocytosis treated with cladribine[END_REF]. On the other hand, the use of such drugs in ISM patients with symptoms refractory to maximal mediator-directed management is still debatable. It is also worth noting that some of the KIT-targeted tyrosine kinase inhibitors (TKIs), like midostaurin, can counteract mediator release in MCs and mediatorrelated symptoms in patients with SM [START_REF] Krauth | Midostaurin (PKC412) inhibits immunoglobulin Edependent activation and mediator release in human blood basophils and mast cells[END_REF][START_REF] Valent | Midostaurin: a magic bullet that blocks mast cell expansion and activation[END_REF]. Moreover, a recent phase 2 trial has demonstrated that midostaurin may be efficacious in ISM patients with severe MCA symptoms refractory to antihistamine medications [START_REF] Van Anrooij | Midostaurin in patients with indolent systemic mastocytosis: an open-label phase 2 trial[END_REF].

Regarding advanced SM, during the 2019 ECNM meeting, data were presented to suggest that only a minority of ASM patients with signs of rapid progression respond to monotherapy with cladribine [START_REF] Barete | Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis[END_REF][START_REF] Akin | Cladribine for mastocytosis: benefits and risks[END_REF]. Correspondingly, most cladribine responders have slowly progressing SM. Patients with slowly progressing ASM without codon 816 KIT mutations may also respond to imatinib or others KIT wild-type-targeting TKIs [START_REF] Georgin-Lavialle | Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor[END_REF][START_REF] Alvarez-Twose | Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature[END_REF]. This is usually not the case in SM patients in whom neoplastic cells display the KIT D816V mutant which confers resistance to these TKIs. For those patients, midostaurin is currently the only drug specifically approved for advanced SM and is often considered as first line treatment option in slowly progressing patients [START_REF] Valent | Midostaurin: a magic bullet that blocks mast cell expansion and activation[END_REF][START_REF] Gotlib | Efficacy and safety of midostaurin in advanced systemic mastocytosis[END_REF][START_REF] Deangelo | Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial[END_REF][START_REF] Kim | Midostaurin: first global approval[END_REF]. However, not all patients with advanced SM respond to midostaurin, especially when the disease is rapidly progressing, whereas other patients relapse during midostaurin [START_REF] Valent | Midostaurin: a magic bullet that blocks mast cell expansion and activation[END_REF][START_REF] Gotlib | Efficacy and safety of midostaurin in advanced systemic mastocytosis[END_REF][START_REF] Deangelo | Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial[END_REF][START_REF] Kim | Midostaurin: first global approval[END_REF], pointing to the need of developing more potent inhibitors. In this context, avapritinib, specifically designed to inhibit KIT D816V, exhibits10-fold more potency against KIT D816V than midostaurin in biochemical assays. In an ongoing phase I trial, patients treated with avapritinib exhibited marked reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase level, spleen volume, and KIT D816V mutant allele burden [START_REF] Deangelo | Clinical activity in a Phase 1 study of Blu-285, a potent, highly-selective inhibitor of KIT D816V in Advanced Systemic Mastocytosis (AdvSM)[END_REF][START_REF] Radia | Avapritinib, a potent and selective inhibitor of KIT D816V, induces complete and durable responses in patients with advanced systemic mastocytosis[END_REF]. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also lowgrade cognitive impairment. Several episodes of small intraparenchymal brain hemorrhages (the majority of which have been identified on imaging and are asymptomatic) have occurred primarily in patients with moderate to severe thrombocytopenia (platelet count <50 x 10 9 /L) [START_REF] Deangelo | Clinical activity in a Phase 1 study of Blu-285, a potent, highly-selective inhibitor of KIT D816V in Advanced Systemic Mastocytosis (AdvSM)[END_REF]. Of note, KIT D816V-negative AHN may develop during treatment with avapritinib [START_REF] Deangelo | Clinical activity in a Phase 1 study of Blu-285, a potent, highly-selective inhibitor of KIT D816V in Advanced Systemic Mastocytosis (AdvSM)[END_REF]. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI. Whatsoever, treatment responses to TKIs are generally still poor in patients with highly aggressive variants of the disease (ASM in transformation and MCL), independent of the type of therapy and age [START_REF] Valent | Advances in the classification and treatment of mastocytosis: current status and outlook toward the future[END_REF][START_REF] Jawhar | Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers[END_REF]. In these patients, poly-chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation (HSCT) is often recommended with the hope to achieve complete remission, despite the fact that not all patients with advanced SM can be cured by HSCT [START_REF] Ustun | Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis[END_REF]. In the future avapritinib and other strong KIT D816V inhibitors may be combined with chemotherapy or even replace chemotherapy or HSCT in such patients. It is also worth noting that numerous patients are not eligible for HSCT because of advanced age or because of comorbidities [START_REF] Ustun | Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis[END_REF]. The remission rate after allo-HSCT is substantially higher in patients with ASM and SM-AHN compared to patients who are suffering from (acute) MCL [START_REF] Ustun | Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis[END_REF]. Moreover, the outcome after HSCT is better and more durable in those who did respond to previous cytoreductive therapy or have stable diseases [START_REF] Ustun | Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis[END_REF]. In each case, the risk of relapse and progression must be balanced against side effects and the risk of transplant-related mortality when discussing HSCT in patients with advanced SM. An open question is whether avapritinib can be used instead of SCT or as preparation for HSCT in patients with advanced SM. Another open question is whether patients eligible for HSCT may benefit from a continuous treatment with a KIT-targeted TKI post-HSCT.

Concluding remarks

Mastocytosis is a rare and complex disease with a heterogeneous clinical presentation and variable prognosis, depending on the variant of the disease and response to treatment. Whereas the KIT D816V mutation alone is detected in indolent SM, additional mutations in other genes are considered to trigger malignant cell growth in advanced SM and to worsen the prognosis in these patients. In CM and ISM, patients suffer primarily from symptoms due to MC-derived mediators, which can manifest as MCAS, whereas in advanced SM, organ impairment is found and is usually an indication to start an interventional antineoplastic therapy. To better understand the pathophysiology of mastocytosis and to establish standards and criteria for classification and prognosis in mastocytosis, the ECNM was established in 2002. Since then, the ECNM has organized a series of Conferences, Workshops, and annual meetings, as well as scientific projects in the field of mastocytosis in Europe, the USA and other non-European countries. In addition, the ECNM has established a registry which includes more than 3800 patients and serves as the basis of several cooperative multicenter studies. In 2019, the Annual ECNM meeting was organized in Salzburg by Karl Sotlar. More than 160 attendees from all parts of Europe and from the USA participated, exchanging ideas and discussing and/or presenting data. Topics of particular interest included (1) new developments in basic and translational science, (2) a better definition and improved diagnostic criteria of mast cell activation and MCAS, (3) new prognostic tools in mastocytosis and (4) new therapeutic concepts in mastocytosis and MCAS. The inter-disciplinary, cooperative network of the ECNM and the newly generated American Initiative in Mast Cell Diseases (AIM) will guarantee that these important topics will be subject of forthcoming studies in preclinical and clinical research and will be translated into clinical practice whenever possible. Updated diagnostic algorithm for patients with a suspected mast cell activation syndrome (MCAS). After the patient has been clinically stabilized, the physician examines potential etiologies and asks for MCAS criteria. If the symptoms are severe and episodic, the likelihood of MCAS is quite high. MCAS consensus criteria are then applied to confirm MC involvement. MCAS criteria can also be applied when the symptoms are less severe and/or atypical. However, in most of these patients, MCAS criteria are not fulfilled. In a next step, the underlying etiology is examined. At this step of the workup, it is important to screen for multiple underlying disorders, since in patients with MCAS, more than one such underlying disease may be present (e.g. mastocytosis and allergy). Regarding mastocytosis, clinical indicators are typical skin lesions, a persistently elevated serum tryptase level and detection of the KIT D816V mutant in peripheral blood cells. According to the underlying condition, MCAS is classified into primary (clonal or genetic) MCAS, secondary MCAS (IgEdependent allergen or non-IgE-dependent trigger), and idiopathic MCAS. In patients with clonal MCAS, the final diagnosis may be CM, SM, or monoclonal MCAS defined by 2 (but not more) minor SM criteria. In a final step, the management plan is established. CM: cutaneous mastocytosis; HαT: hereditary alpha-tryptasemia; MC: mast cell; MCA: mast cell activation; MMAS: Monoclonal/primary MCAS; SM: systemic mastocytosis. Adapted from Valent et al. [START_REF] Valent | Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome[END_REF].

Table 3

Variants of mast cell activation syndrome. Leuk Lymphoma. Author manuscript; available in PMC 2021 May 01.

Mast cell activation syndrome (MCAS) variant

Key diagnostic variables

Figure 1 .

 1 Figure 1.

  Primary MCAS KIT D816V-mutated clonal MCs are found in most cases and also display CD25; also reported in cases with KIT-mutated mast cells and hereditary alpha-tryptasemia a Synonyms for KITGOF mutation-associated MCAS: Clonal MCAS Monoclonal MCAS (MMAS) (a) With cutaneous mastocytosis (CM) CM criteria fulfilled; SM criteria not fulfilled (b) With systemic mastocytosis (SM) SM criteria fulfilled (c) With only 2 minor SM criteria Criteria to diagnose CM or SM not fulfilled Secondary MCAS Triggered by an allergen to which a subject is sensitive or to an non-IgE-dependent trigger of MC activation Idiopathic MCAS MCAS criteria are fulfilled, but no underlying reactive disease, no IgE-mediated allergy, and no monoclonal mast cells are detectable a GOF: gain of function. a In these patients, no activating KIT mutation at codon 816 is detected, and when tested, flow cytometry usually confirms the presence of CD25negative (normal) mast cells.

Leuk Lymphoma. Author manuscript; available in PMC 2021 May 01.

Funding

Karin Hartmann receives research support from Euroimmun and Thermofisher. Karl Sotlar receives research support by Novartis. Peter Valent is supported by the Austrian Science Funds (FWF) project F4704-B20. The other authors declare no funding in relation with the manuscript.

Table 1

The 2016 World Health Organization (WHO) classification for mastocytosis.

Categories

Consensus criteria of the EU/US group for the diagnosis of mast cell activation syndrome (MCAS).

Criterion The Mutation-Adjusted Risk Score (MARS) for advanced SM. Leuk Lymphoma. Author manuscript; available in PMC 2021 May 01.


Toshiki Gushi

Matic Jovičević Klug

J Peña-Garcia

Sambit Ghosh

Jean-Philippe P Attané

Hanako Okuno

Olivier Fruchart

Jan Vogel

Takashi Suemasu

Stefania Pizzini
email: stefania.pizzini@neel.cnrs.fr

José Peña Garcia

Laurent Vila
email: laurent.vila@cea.fr

Large Current Driven Domain Wall Mobility and Gate Tuning of Coercivity in Ferrimagnetic Mn4N Thin Films

Keywords: spintronics, spin transfer torque, magnetic domain walls, nitrides thin films, Kerr microscopy, micromagnetism

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The development of artificial intelligence and big data require the development of high-speed and lowpower memories and processors. In this context, spintronics, which aims at using the electron spin to carry and manipulate data, possesses compelling advantages over competing technologies: intrinsic non-volatility, room-temperature operation, and compatibility with the CMOS technology. It has thus been shown to possess the potential to disrupt not only the memory market, with the on-going commercialization of non-volatile magnetic memories such as MRAMs, but actually the whole information technology market, through the creation of post-CMOS 1 or of neuromorphic technologies [START_REF] Torrejon | Neuromorphic computing with nanoscale spintronic oscillators[END_REF] .

Spintronics Achilles' heel might be its hazardous dependence on cobalt, rare-earth elements, and heavy metals (especially tungsten and platinum). These materials are indeed based on elements identified as critical by the government agencies of developed countries, because of the likelihood and impact of supply shortfalls, and of various geopolitical and environmental factors [START_REF] Chakhmouradian | From "strategic" tungsten to "green" neodymium: A century of critical metals at a glance[END_REF][START_REF]Communication from the commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions[END_REF] .

In this work, we will describe the magnetic properties of a material, made of abundant and cheap elements, and show that it is a promising candidate for the development of a sustainable spintronics: epitaxial Mn4N films. Beyond features such as a perpendicular magnetisation, or a large Extraordinary Hall Effect (EHE), we show that in this material record current driven domain wall velocities can be obtained at room temperature. Whereas in the past years the whole spintronics community shifted its focus from spin-transfer torques to spin-orbit torques, these results show that classical spin-transfer torques remain highly competitive for current-induced DW motion. Also, we show that the coercivity of Mn4N films can be easily tuned by a gate voltage, this ability constituting a tool for DWs, nanomagnets or skyrmion manipulation.

Mn4N is one of the few known magnetic nitrides. While bulk magnetic nitrides have been studied in the 1960's and 1970's [START_REF] Coey | Magnetic nitrides[END_REF] , only a few groups have succeeded in growing magnetic nitrides thin films, on MgO or SrTiO3 (STO) substrates, using molecular beam epitaxy 6 , 7 , pulsed laser deposition [START_REF] Shen | Metallic transport and large anomalous hall effect at room temperature in ferrimagnetic Mn4N epitaxial thin film[END_REF] or magnetron sputtering [START_REF] Kabara | Perpendicular magnetic anisotropy of Mn4N films fabricated by reactive sputtering method[END_REF] . They grow in the anti-perovskite structure depicted in Figure 1a, with a central N atom, surrounded by metal atoms located on two inequivalent atomic sites, and antiferromagnetically coupled.

These films present a very large technological interest: they are made of only abundant elements, which responds to the increasing need for sustainable and low cost electronics. They are ferrimagnets with a low spontaneous magnetisation Ms, which should allow increasing the efficiency of spin transfer and spin orbit torques. This should facilitate magnetisation manipulation, increase the switching speed and lower the power consumption of spintronic devices. The small spontaneous magnetisation also provides a relatively small sensitivity to externally applied magnetic fields: ferrimagnetic-based devices do not need to be magnetically shielded when embedded in memory or computational devices, and the production of stray fields is minimized. The Curie temperature of the bulk compound is 745K 10 .

Among the magnetic nitride series, Mn4N holds a characteristic that is much looked for in spintronics: in appropriate growth conditions, it presents a perpendicular magnetisation. This property, associated to the low Ms, allows foreseeing high current-driven domain wall speeds by spin transfer torques [START_REF] Emori | Enhanced current-induced domain wall motion by tuning perpendicular magnetic anisotropy[END_REF] .

Here, 10 nm thick films were grown epitaxially on an STO(001) substrate. As recently observed [START_REF] Gushi | Millimeter-sized magnetic domains in perpendicularly magnetized ferromagnetic Mn4N thin films grown on SrTiO3[END_REF] , the small lattice mismatch between the film and the substrate allows obtaining a high crystalline quality. The X-Ray Diffraction (XRD) spectra of Figure 1b demonstrates the epitaxial growth on the STO substrate with a (001) texture. The quality of this epitaxial growth is also evidenced by ω-scan rocking curves and RHEED diffraction (cf. Methods). The typical RMS roughness of the layer, measured by Atomic Force Microscopy, is smaller than 0.7 nm. The Scanning Transmission Electron Microscopy images of the Mn4N epilayer, shown in Figures 1c and1d, give further evidence of its very high crystalline quality, the absence of dislocations and the perfect epitaxy and its sharp interface with the Ti terminated STO.

The magnetic properties of the films were studied by Vibrating Sample Magnetometry, SQUID and transport measurements. The extracted spontaneous magnetisation is small (MS=7.1 x 10 4 A/m), whereas the uniaxial magnetic anisotropy is large enough (Ku= 1.1 x 10 5 J/m 3 ) to obtain perpendicular magnetisation. The hysteresis loop measured by extraordinary Hall effect (Figure 1e) shows 100% remanence. As the magnetic field acts on the magnetisation through a -µ 𝑂 𝐻 ⃗ ⃗ . 𝑀 ⃗⃗ Zeeman energy density, one can expect this material, which possesses a small Ms, to exhibit a large coercive field. The coercivity remains however quite low (170 mT). Also, Magneto-Optical Kerr microscopy observations of the magnetic domain structure have been made for partially reversed states (cf. Figure 1.f). The observed scarce nucleation centers with remarkably large domains, at the millimeter scale, with smooth and very long DWs [START_REF] Gushi | Millimeter-sized magnetic domains in perpendicularly magnetized ferromagnetic Mn4N thin films grown on SrTiO3[END_REF] , result from the high crystalline quality. Mn4N films are metallic, with layer resistivity around 180 µ cm at room temperature, comparable to CoFeB-based materials. Although Mn4N is made of only light elements, its Extraordinary Hall Effect angle is large (around 2%), comparable to that of materials with strong spin-orbit coupling such as FePt or TbCoFe [START_REF] Moritz | Extraordinary hall effect in thin magnetic films and its potential for sensors, memories and magnetic logic applications[END_REF] . The efficiency of the spin-transfer torque was first studied by extraordinary Hall measurements, using DC currents and quasi-static fields in the device geometry depicted in Figure 2a. As seen in Figure 2b, the Mn4N layer was patterned by ion milling into 0.5 µm wide Hall bars, with a constriction patterned in between the two Hall crosses (cf. § Methods). The patterning induces a sharpening of the switching, with very square hysteresis loops (cf. Figure 2d). The minor loops show that the threshold field for DW propagation remains low, around 0.15 T. This field can be compared to the critical current density required to induce DW motion. As seen in Figure 2c, the application of a DC current allows inducing the DW motion at zero field, for a current density of 1.2x10 [START_REF] Emori | Enhanced current-induced domain wall motion by tuning perpendicular magnetic anisotropy[END_REF] A/m 2 . The DW is then depinned from a notch, and propagates over more than 5 µm before getting pinned at the cross. The spin transfer efficiency, i.e., the ratio between the typical propagation field and the DC current required to induce DW motion, is thus around 1.2510 -12 Tm²/A. This value is two orders of magnitude higher than that of NiFe, and similar to that of systems with heavy elements and large spin-orbit coupling such as FePt [START_REF] Nguyen | Elementary depinning processes of magnetic domain walls under fields and currents[END_REF] , or of TbCoFe and CoGd ferrimagnets [START_REF] Boulle | Current-induced domain wall motion in nanoscale ferromagnetic elements[END_REF] .

Note that in most magnetic thin films studied in the last years, the DWs were moved by the Spin-Orbit Torque (SOT) arising from the growth on a Spin-Hall effect material, and from the presence of the interfacial Dzyaloshinskii-Moriya interaction (DMI) which favours chiral Néel walls 16 , 17 , 18 . On the contrary, DW motion is driven here by the classical Spin Transfer Torque (STT): since the Mn4N layer is thick (10 nm), interfacial effects should be negligible, even in the presence of an interfacial DMI. The DW propagates in the direction of the electron flow, which is consistent with this interpretation. In order to rule out the contribution of spin-orbit torques to the DW dynamics, we carried out Kerr microscopy measurements of domain wall motion under in-plane magnetic field, which demonstrated the absence of DMI in our system (cf. Supporting Information).

The efficiency of the spin transfer torque was also investigated by measuring directly current-driven DW velocities by Kerr microscopy as shown in Figure 3a and 3b. A 10 nm thick Mn4N layer was patterned into 10 µm long, 2 µm and 1 µm wide strips. Several wires were connected in parallel via a large injection pad, in order to optimize the impedance matching with the voltage generator, and to obtain a statistically relevant measurement of the DW velocity.

DWs can be created using an out-of-plane field pulse, leading to one DW per wire. Current pulses of durations ranging from 1 to 3 ns, with current densities up to 1.5x10 [START_REF] Gushi | Millimeter-sized magnetic domains in perpendicularly magnetized ferromagnetic Mn4N thin films grown on SrTiO3[END_REF] A/m 2 were then applied to induce DW motion. The differential images of Figures 3a and3b allow measuring the distance over which the DWs have propagated during the pulse, therefore giving access to the average DW velocity, for 2 µm and 1 µm wide strips respectively. The limited dispersion of the DW displacements among the nanowires points out that DWs are weakly pinned by defects (i.e., the behaviour is not stochastic).

Figure 3c shows the variation of the domain wall velocity as a function of the current density. The behaviours are nearly identical for 1µm and 2µm wide strips. For low current densities J, in the thermally activated regime where the DW movement is hindered by defects, the speed changes exponentially with J. Above around J=8.5x10 [START_REF] Emori | Enhanced current-induced domain wall motion by tuning perpendicular magnetic anisotropy[END_REF] A/m 2 , the DW speed starts varying linearly with J, and very high DW velocities (up to 900 m/s) are reached for 1.3x10 [START_REF] Gushi | Millimeter-sized magnetic domains in perpendicularly magnetized ferromagnetic Mn4N thin films grown on SrTiO3[END_REF] A/m 2 , in the direction of the electron flow.

Such high DW velocities deserve some discussion. Current driven domain wall motion by STT has been observed in thin films with both in-plane [START_REF] Hayashi | Current driven domain wall velocities exceeding the spin angular momentum transfer rate in permalloy nanowires[END_REF][START_REF] Uhlíř | Current-induced motion and pinning of domain walls in spin-valve nanowires studied by xmcd-peem[END_REF] and out-of-plane magnetisation. In in-plane magnetized films of permalloy, the measured DW velocities are typically of the order of 100 m/s, for currents densities around 1.5x10 [START_REF] Gushi | Millimeter-sized magnetic domains in perpendicularly magnetized ferromagnetic Mn4N thin films grown on SrTiO3[END_REF] A/m 2 . However, in these systems the DW motion is largely affected by pinning, and in general a wide dispersion of DW displacements is observed even in the flow regime [START_REF] Uhlíř | Current-induced motion and pinning of domain walls in spin-valve nanowires studied by xmcd-peem[END_REF] . Moreover, since DWs are wide (>100nm) in these in-plane systems, the interest for applications to logic and storage devices is limited. Quite high spin transfer efficiencies have been measured in systems with perpendicular magnetic anisotropy (PMA) such as Co/Ni or FePt [START_REF] Burrowes | Non-adiabatic spin-torques in narrow magnetic domain walls[END_REF] , but in these systems DW motion at zero field is usually hindered by pinning, which induces a large coercivity and a stochastic behaviour. In Pt/Co/Pt, DWs could not be moved by STT, due to the limited spin polarisation within the Co layer [START_REF] Cormier | Effect of electrical current pulses on domain walls in Pt/Co/Pt nanotracks with out-of-plane anisotropy: Spin transfer torque versus joule heating[END_REF] . On the other hand, very high DW mobilities were found in magnetic semiconductor films such as (Ga,Mn)(As ,P) for very low current densities [START_REF] Curiale | Spin drift velocity, polarization and current-driven domain-wall motion in (Ga, Mn)(As, P)[END_REF][START_REF] Adam | Nonadiabatic spin-transfer torque in (Ga, Mn) As with perpendicular anisotropy[END_REF] . However these measurements were done at low temperature, and the current density was limited to some 10 10 A/m 2 , with a maximum speed of 30m/s at 10 10 A/m 2 .

Although in recent years the community has focused nearly entirely on SOT-driven DW dynamics, the giant DW velocities obtained in Mn4N, show that the STT can be competitive with SOT. SOT has been found to be an efficient mechanism to drive DWs in non-centrosymmetric multilayers, in which a FM is deposited on a heavy metal like Pt [START_REF] Emori | Current-driven dynamics of chiral ferromagnetic domain walls[END_REF][START_REF] Ryu | Chiral spin torque at magnetic domain walls[END_REF] . The prototypical example is Pt/Co(0.6nm)/AlOx [START_REF] Miron | Fast current-induced domain-wall motion controlled by the Rashba effect[END_REF] where the chiral Néel structure acquired by the DWs in the presence of interfacial Dzyaloshinskii-Moriya interaction [START_REF] Thiaville | Dynamics of Dzyaloshinskii domain walls in ultrathin magnetic films[END_REF] leads to a high mobility (v=400m/s for J=310 [START_REF] Gushi | Millimeter-sized magnetic domains in perpendicularly magnetized ferromagnetic Mn4N thin films grown on SrTiO3[END_REF] A/m 2 ) with a satisfying reproducibility of the DW movements. Higher SOT-driven DW mobilities were obtained recently in a multilayer structure in which two Co/Ni layers were coupled anti-ferromagnetically through a Ru layer [START_REF] Yang | Domain-wall velocities of up to 750 m s-1 driven by exchange-coupling torque in synthetic antiferromagnets[END_REF] , or in GdCo ferrimagnet layers deposited on top of Pt [START_REF] Caretta | Fast current-driven domain walls and small skyrmions in a compensated ferrimagnet[END_REF] . In these systems the DW velocity was clearly observed to vary with the total magnetisation. In the former experiment, a maximum velocity of v=750 m/s for J=3x10 [START_REF] Gushi | Millimeter-sized magnetic domains in perpendicularly magnetized ferromagnetic Mn4N thin films grown on SrTiO3[END_REF] A/m 2 was obtained at room temperature using a Ru spacer layer, so that the stack magnetisation was reduced to 8% of the spontaneous magnetisation of a single Co/Ni layer. In the latter one, a peak velocity of 1250 m/s was reported at 240 K (the angular moment compensation temperature) for a current density of 2x10 [START_REF] Gushi | Millimeter-sized magnetic domains in perpendicularly magnetized ferromagnetic Mn4N thin films grown on SrTiO3[END_REF] A/m 2 .

In this context, the velocities presented here at room temperature for DWs in Mn4N are comparable to the best results obtained using SOTs. Moreover, they represent the first demonstration of very efficient current-driven DW motion by pure STT using a system with PMA.

In order to understand the microscopic origins of the high current-induced DW velocities achieved in Mn4N thin films, we have considered the analytical expression of the STT in the adiabatic limit. In a perfect nanowire with out-of-plane magnetisation, the 1D model describes well the main features of the DW velocity under a spin-polarised current [START_REF] Fukami | Micromagnetic analysis of current driven domain wall motion in nanostrips with perpendicular magnetic anisotropy[END_REF][START_REF] Szambolics | Domain wall motion in ferromagnetic systems with perpendicular magnetization[END_REF] .

Magnetisation dynamics is governed by the Landau-Lifshitz-Gilbert equation (LLG), with additional terms taking into account the effect of spin-polarised current on the magnetisation. In ferrimagnetic systems, the LLG equation needs to be modified close to the compensation temperature when the Landé factors of the two magnetic sublattices are very different [START_REF] Caretta | Fast current-driven domain walls and small skyrmions in a compensated ferrimagnet[END_REF][START_REF] Kim | Fast domain wall motion in the vicinity of the angular momentum compensation temperature of ferrimagnets[END_REF] . Since the orbital moment of Mn is close to zero, the Landé factors should be very similar (close to 2) for both sublattices in Mn4N. Moreover, the temperature variation of the magnetization does not reveal any compensation temperature. The DW dynamics close to room temperature should thus be very similar to the dynamics of a ferromagnetic system [START_REF] Komori | Magnetic and magneto-transport properties of Mn4N thin films by Ni substitution and their possibility of magnetic compensation[END_REF] . In our system with PMA and negligible Dzyaloshinskii-Moriya interaction, the DWs are expected to be in the Bloch configuration at rest (see Supporting Information). In the adiabatic limit of current-driven dynamics, the DW can move continuously only when its magnetisation can start precessing in order to align with the spin polarisation of the incoming conduction electrons (i.e., along z in a system with PMA). To do so, the DW energy has to overcome the anisotropy energy KD given by the difference in energy between the Bloch and the Néel DW configurations. This occurs above a threshold critical current density 𝐽 𝑐 :

𝐽 𝑐 = 2𝑒 ℏ𝑃 Δ(𝜑)𝐾 𝐷 , ( 1
)
where P is the spin polarisation of the conduction electrons, Δ(𝜑) is the DW width as a function of the tilt angle 𝜑, the angle between the magnetisation in the center of the DW and the DW plane. The anisotropy energy KD depends on the sample geometry and on the spontaneous magnetisation (see Supporting Information). Using the experimental strip geometry (1 µm wide and 10nm thick) and the material parameters measured experimentally for the Mn4N film (𝑀 𝑠 = 7.1 x 10 4 A/m, 𝐾 𝑢 = 0.11 x 10 6 J/m 3 and taking 𝐴 = 10 pJ/m (value extracted by scaling the Curie temperature to that of other nitride compounds) and P = 0.8, the critical current density is expected to be 𝐽 𝑐 ≈ 1.9x10 10 A/m 2 . This is much lower than that of permalloy strips with in-plane magnetisation (𝐽 𝑐 ≈ 10 13 A/m 2 ) [START_REF] Emori | Enhanced current-induced domain wall motion by tuning perpendicular magnetic anisotropy[END_REF] .

While a non-adiabatic torque has been invoked to explain the DW motion observed experimentally in permalloy strips well below 𝐽 𝑐 , in our case the observed DW motion occurs for current densities well above Jc and can therefore be explained in terms of the adiabatic torque alone. 32,33 . As seen in the Supporting Information, when 𝐽 ≫ 𝐽 𝑐 the adiabatic torque drives the DWs with a velocity given by:

𝒗 ≈ 1 1 + 𝛼 2 |𝒖| ( 2
)
where 𝒖 = 𝑔𝜇 𝐵 2𝑒𝑀 𝑠 𝑃𝑱 is the spin-drift velocity, parallel to the electron flow.

From Equation 2, the mobility 𝑣/𝐽 is proportional to the ratio P/Ms of the spin polarisation and the spontaneous magnetisation, with a negligible dependence on the damping parameter, 𝛼 =0.15 as measured by time-resolved Kerr spectroscopy. The spin polarisation P is then the only fitting parameter and an estimation of its value in Mn4N can be obtained from the comparison between the experimental DW velocities and the result of Equation 2 in which P is varied. Experimentally, a linear regime indeed appears in the speed versus current density curve above the thermally activated regime. The best agreement between experiments (Figure 3c) and 1D model (Figure 3d) is obtained using a polarisation value around P=0.8 (+/-0.1), close to the polarisation of the density of states obtained using first-principle calculations [START_REF] Miao | Electronic structure and magnetic properties of Mn3 GaN precipitates in Ga 1-x Mn x N[END_REF] . We can then conclude that the large domain wall speeds observed for Mn4N are due to the conjunction of the small value of the spontaneous magnetisation and of the high spin polarisation.

In order to confirm the different features predicted by the 1D model we have also performed micromagnetic simulations (see Supporting Information). The results reported in Figure 3d show an overall agreement of the 1D model with the 2D simulations.

Note that in our simulations we have neglected the effect of the non-adiabatic torque on the DW velocity. While this term had to be introduced to explain the DW dynamics in in-plane magnetized systems [START_REF] Hayashi | Current driven domain wall velocities exceeding the spin angular momentum transfer rate in permalloy nanowires[END_REF] below the intrinsic depinning current density, it has actually a much lower influence on the DW velocity in our system.

Below the critical current density 𝐽 𝑐 , the presence of the non-adiabatic torque results in a steady regime motion, with a velocity 𝑣 = 𝛽 𝛼 𝑢. This effect is not observable in our system, as the critical current 𝐽 𝑐 is extremely small and obscured by the creep regime. Above 𝐽 𝑐 , in the precessional regime, a term 𝑎𝛽 1+𝑎 2 𝑢 has to be added to the velocity of Equation 2. However, since 𝛼 is much smaller than unity, this extra term is negligible with respect to the adiabatic term. Although the measurement of the non-adiabatic term has been the subject of severe debates [START_REF] Boulle | Current-induced domain wall motion in nanoscale ferromagnetic elements[END_REF] , its main effect is to explain the presence of DW motion below the critical current density. Here we show that the adiabatic torque alone can explain the measured DW speeds down to low current densities, because of the small critical current densities characteristic of PMA systems with small MS. This point is further discussed in the Supporting Information, where we also study the hypothesis according to which 𝛼 = 𝛽.

The last property we would like to address is the effect of the electric field on the anisotropy of the Mn4N layer shown in Figure 4. A back gate voltage was applied to the bottom of the 300 µm STO substrate, while measuring the coercivity of a 4.2 nm-thick Mn4N layer with a magnetic field (cf. § Methods). The measurements were performed at 10 K, so that the dielectric constant of STO reaches very high values (30 000). The gate voltage acts on both the negative and positive parts of the magnetic hysteresis, the coercivity varying linearly with the applied voltage, see Figure 4e. By assuming that the coercivity variations correspond to variations of the anisotropy energy [START_REF] Weisheit | Electric field-induced modification of magnetism in thin-film ferromagnets[END_REF] , the efficiency of the electric field effect can be written 𝜂 = , where 𝐸 𝑘 /𝑆 is the anisotropy energy per surface, and 𝐻 𝐶 the coercive field. In our system, 𝜂 reaches a value of -15 pJ/(V.m). This very large efficiency, which could be further enhanced by using thinner Mn4N films, requires further in-depth studies to be understood. In particular, it is possible that a strain-based mechanism adds up to the charge transfer mechanism, due to the STO substrate behaviour in the low-temperature tetragonal phase 36 , 37 , 38 . Whatever the mechanism, this value is up to now only approached in systems with much thinner magnetic layers [START_REF] Nakazawa | Electric field control of magnetic anisotropy in a Co/Pt bilayer deposited on a high-κ SrTiO3[END_REF] .

Conclusion

In conclusion, Mn4N/STO films present several properties that make them compelling candidates for spintronics applications. They are characterized by a perpendicular magnetisation, and notwithstanding the absence of heavy elements with high spin-orbit coupling, they exhibit a large extraordinary Hall effect. We showed in this system efficient current-induced domain wall motion, simply due to the adiabatic spin-transfer torque. The observed domain wall velocities largely surpass those obtained using spin transfer torques up to now, and is at least comparable to the best results reported for non-centrosymmetric stacks with interfacial DMI. We show that the low critical current is a consequence of the PMA and of the low magnetisation of the ferromagnetic material, which leads to a low barrier for precession of the DW magnetisation. high DW mobility observed in the linear regime is a consequence of the small magnetisation and of the high spin polarisation. Finally, we demonstrate the possibility to control the magnetic anisotropy of Mn4N films using electric fields. As Mn4N is made of cheap and abundant elements, and does not include critical materials such as precious metals and rare-earths, it appears as a worthy candidate for sustainable spintronics applications. Future developments of this work may include the substitution of Mn by other 3d magnetic elements, in order to tailor the magnetic parameters, and for instance to reach the compensation point.

Methods

Sample growth

The Mn4N thin films were grown on STO(100) substrates by plasma-assisted molecular beam epitaxy (MBE), as in refs. , [START_REF] Yasutomi | Perpendicular magnetic anisotropy of Mn4N films on MgO (001) and SrTiO3 (001) substrates[END_REF][START_REF] Ito | Perpendicular magnetic anisotropy in co x mn4-x n (x= 0 and 0.2) epitaxial films and possibility of tetragonal mn4n phase[END_REF] . During the deposition, the substrate temperature was kept at 450 °C, to allow the diffusion of Mn and N atoms coming from the Mn solid source of a Knudsen-cell and from the radio-frequency (RF) N2 plasma. We optimised the growth condition by using a Mn deposition rate of 1.5 nm/min, a N2 gas flow of 1.0 cm 3 /min, a pressure in the chamber of 4.5×10 -3 Pa, and an input power of 105 W. The samples were capped with SiO2 for the CIDWM experiments, and with Ta for the voltagecontrol of the magnetic anisotropy experiments, using a sputtering gun installed in the MBE chamber.

XRD/RHEED

The Mn4N films were characterized in-situ by RHEED, with the 20 keV electron beam azimuth along the STO [100] direction. The diffraction pattern of anti-perovskite nitride consists of fundamental and superlattice diffraction peaks, similarly to what has been simulated for Fe4N thin film [START_REF] Ito | Growth and magnetic properties of epitaxial Fe4N films on insulators possessing lattice spacing close to Si (001) plane[END_REF] . Our sample showed streaky RHEED patterns with obvious superlattice diffraction lines, which are sharper and surrounding the central line, indicating the presence of well ordered N atoms at the body center of the fcc Mn lattice.

The crystalline quality was also evaluated by ω-2θ (out-of-plane), φ-2θχ (in-plane) XRD and ω-rocking curve measurement, using Cu Kα radiation in a Rigaku Smart Lab®. For the in-plane diffraction, the incidence angle ω was fixed as 0.4°, and the scattering vector Q was also set along STO [100] and [110]. The ω-rocking curve at the Mn4N[004] peak exhibits a remarkably small full width at half maximum of 0.14°, highlighting the very high crystalline quality of the epilayer [START_REF] Gushi | Millimeter-sized magnetic domains in perpendicularly magnetized ferromagnetic Mn4N thin films grown on SrTiO3[END_REF] . The thickness of the layer was also measured by X-ray reflectometry.

AFM

The surface state was observed using a Bruker Dimension in the oscillating mode. The root mean square roughness (0.7 nm) has been evaluated on a 4×4 μm 2 area. TEM Scanning transmission electron microscopy (STEM) measurements have been carried out using a Cscorrected FEI Themis at 200 keV. High angle annular dark field (HAADF)-STEM images were acquired using a convergence semiangle of 20 mrad and collecting scattering >65 mrad. The STEM specimen was prepared by the FIB lift-out technique using a FEI dual-beam Strata 400S at 30 kV.

VSM/SQUID

The magnetisation and magnetic anisotropy were measured by Quantum design MPMS® 3 with outof-plane (1.5 T) and in-plane (7 T) magnetic fields. The anisotropic energy Ku was calculated from the area enclosed in-between the out-of-plane and in-plane magnetisation curves.

EHE and voltage control of the anisotropy

Extraordinary Hall effect loops and resistivity measurements were performed using the Van der Pauw method for blanket layers at 10K, in a cryostat placed in-between the poles of a 1.2 T electromagnets. The 4 corners of the sample were wire-bonded using Al wires. A back gate voltage up to ±200 V was applied by sticking the sample to the sample holder with silver paint.

Domain wall speed measurements

The Mn4N films were processed into 1 and 2-μm-wide strips by electron beam lithography and Ar ion milling technique, using lifted-off Al patterns as etching masks. The contact electrodes consist in a Ti/Au/Ti stack. The domain wall velocities were measured using Magneto-Optical Kerr microscopy. After saturation of the magnetisation, high field pulses were applied in the reversed direction to nucleate a domain in the injection pad and to inject domain walls into the nanostrips. The domain walls were then displaced using current pulses generated by a voltage generator, able to provide voltage pulses up to 80V in amplitude and down to 500 ps in duration. The domain wall velocities were calculated by dividing the domain wall displacement by the pulse length full width half maxima, measured by an oscilloscope connected in series with the sample. Further verification of the DW speeds was done for some current density values by measuring the DW displacement x for different current pulse durations t, and extracting the DW velocity from the slope of the curve x vs. t.

Figure 1

 1 Figure 1 (a) Scheme of the anti-perovskite structure of Mn4N films. The metallic ions located at the corners and at the centers of the faces are antiferromagnetically coupled. (b) Out-of-plane (top) and in-plane (bottom) XRD spectra of a Mn4N(10 nm)/STO deposit, with Kiessig fringes testifying of the crystalline quality. The in-plane XRD measurements were performed by setting the scattering vector along STO[100] (red) and STO[110] (blue). Asterisks correspond to the STO substrate diffraction peaks. (c) Scanning Transmission Electronic image of the Mn4N/STO sample corroborating the crystalline quality of Mn4N. (d) Higher magnification image showing the perfect epitaxy of the Mn4N with the Ti terminated STO interface and its sharpness, any dislocation is observed on the TEM specimen. (e) Hysteresis loop measured by Extraordinary Hall effect, for an applied field perpendicular to the surface. (f) Magneto-optical Kerr microscopy observation of the sample in a partially reversed state of magnetisation (M/MS=-0.1). The reversed domain appears in black.

Figure 2

 2 Figure 2 (a) Schematics of the device and of the probe connection (b) SEM images (top) of the constriction before etching, and AFM image (bottom) after etching. (c) Room temperature Hall voltage recorded at the left Hall cross as a function of the applied current density. The DW is firstly pinned on the constriction. It is then depinned by the current, and finally propagates within the left Hall cross, causing a partial reversal (64%) of the magnetisation. (d) Hall voltage of the first Hall cross obtained when increasing the field from 0 to positive values, the starting point being the final state of fig. (c). This confirms that after the application of the DC current in (c), the DW is indeed located in the Hall cross.

Figure 3

 3 Figure 3 (a) and (b): differential MOKE images showing the displacement of several DWs in 2um (a) and 1um wide Mn4N strips (b) after 10 x 1ns current pulses. The current density is respectively  0.4 and  1.05 x 10 12 A/m 2 and the strips are 10 µm long. The black contrast corresponds to the zone over which the DWs moved during the current pulses. (c) Domain wall velocity vs. current density measured for 1 and 2 µm-wide strips. The domain wall velocity reaches an average above 900 m/s at 1.3x10 12 A/m². The dotted line is a guide to the eye to emphasize the linear regime. The inset shows an example of 1 ns current pulse measured with an oscilloscope in series with the sample. (d) Theoretical DW velocity (red line) obtained using the 1D model (equation 3) using the experimental magnetic parameters (Ms and Ku) and taking P=0.8 (giving the best agreement between experimental and theoretical DW mobility, see below) and α=0.15 as determined by time resolved Kerr measurements. The black dots are the results of micromagnetic simulations using the same parameters. The inset is a zoom of the low current density regime.

Figure 4

 4 Figure 4 (a) Schematics of the experiments. A gate voltage is applied to the back of the STO substrate, while the top electrical contacts, arranged in a Van der Pauw configuration, are used to measure the EHE of the Mn4N layer. (b) Hysteresis loops recorded for various applied back gate voltages. (c) and (d) Zoom of the figure b close to the coercive field, for negative (c) and positive (d) applied fields, using the same color code for the gate voltage. (d) Evolution of the coercivity with the applied gate voltage, for both the positive (top) and negative (bottom) halfloop.

Acknowledgments

We acknowledge N. Mollard for the TEM specimen preparation. The devices were prepared in PTA platform from Grenoble, with partial support from the French RENATECH network. This work received support from the French ANR programme through projects OISO (ANR-17-CE24-0026-03), TOPRISE (ANR-16-CE24-0017) and the Laboratoire d'Excellence LANEF (ANR-10-LABX-51-01) in Grenoble. TG acknowledge JSAP support. JPB acknowledges the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 754303. We acknowledge Prof. Isogami from the NIMS in Japan, for the measurement of the damping parameter.

Author contributions

The experiments were performed by T. G., M. J. K. and S.G., and the simulations by J. P. G. H. O. performed the TEM study. The work has been supervised by L.V., T.S., O.F., S.P., J.P.A. and J.V. All coauthors discussed the results, L.V., J.-P. A. and S.P. wrote the manuscript with the input of all the authors.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at Evidence of absence of Spin Orbit Torques; discussion on field and current driven domain wall dynamics; influence of the non-adiabatic torque and of the damping parameter on the current-induced DW motion; damping and non-adiabatic torque in the particular case for which α=β; simulations details.