Inferring the dynamic of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms

Matthieu Mosca (1) , Gurvan Hermange (2) , Amandine Tisserand (1) , Robert John Noble (3, 4) , Christophe Marzac (1) , Caroline Marty (1) , Cécile Le Sueur , Hugo Campario (5) , Gaëlle Vertenoeil (6, 7) , Mira El-Khoury (1) , Cyril Catelain (8) , Philippe Rameau (8) , Cyril Gella , Julien Lenglet (9) , Nicole Casadevall (1) , Remi Favier (10) , Eric Solary (1, 11) , Bruno Cassinat (12) , Jean-Jacques Kiladjian (12) , Stefan Constantinescu (7) , Florence Pasquier (1) , Michael Hochberg (4) , Hana Raslova (1) , Jean-Luc J.-L. Villeval (1) , François Girodon , William Vainchenker (1) , Paul-Henry P.-H. Cournède (2) , Isabelle Plo (1)

1 CSHMyelo - U1287 Inserm - Cellules souches hématopoïétiques et développement des hémopathies myéloïdes
2 MICS - Mathématiques et Informatique pour la Complexité et les Systèmes
3 IEU - Department of Evolutionary Biology and Environmental Studies
4 UMR ISEM - Institut des Sciences de l'Evolution de Montpellier
5 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
6 Ludwig Institute for Cancer Research
7 UCL - Université Catholique de Louvain = Catholic University of Louvain
8 AMMICa - Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
9 Hôpital Privé d'Antony
10 CHU Trousseau [APHP]
11 U1170 Inserm - Hématopoïèse normale et pathologique
12 IRSL - Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine ; ex- Institut Universitaire Hématologie-IUH)

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem cells (HSC) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon alpha (IFNα) has demonstrated some efficacy in inducing molecular remission in MPN. In order to determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in MPN patients by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured several times per year the clonal architecture of early and late hematopoietic progenitors (84,845 measurements) and the global variant allele frequency in mature cells (409 measurements). Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSC. Our data support the hypothesis that IFNα targets JAK2V617F HSC by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSC and increases with high IFNα dosage in heterozygous JAK2V617F HSC. Besides, we found that the molecular responses of CALRm HSC to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and high dosage of IFNα correlates with worse outcomes. Together, our work indicates that the long-term molecular efficacy of IFNα implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNα dosage.

Domaines: Bio-informatique [q-bio.QM]; Cancer; Statistiques [math.ST]

Matthieu Mosca, Gurvan Hermange, Amandine Tisserand, Robert John Noble, Christophe Marzac, et al.. Inferring the dynamic of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms. Blood, 2021, ⟨10.1182/blood.2021010986⟩. ⟨hal-03452002⟩