51. Inferring the dynamic of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms
- Author
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Cécile Le Sueur, François Girodon, Matthieu Mosca, Stefan N. Constantinescu, Cyril Catelain, Rémi Favier, Hana Raslova, Julien Lenglet, Bruno Cassinat, Robert Noble, Christophe Marzac, Hugo Campario, Florence Pasquier, Philippe Rameau, Caroline Marty, Amandine Tisserand, Gurvan Hermange, Cyril Gella, Isabelle Plo, Gaëlle Vertenoeil, Paul-Henry Cournède, Mira El-Khoury, Jean-Jacques Kiladjian, Jean-Luc Villeval, William Vainchenker, Eric Solary, Michael E. Hochberg, Nicole Casadevall, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Mathématiques et Informatique pour la Complexité et les Systèmes (MICS), CentraleSupélec-Université Paris-Saclay, Institute of Evolutionary Biology and Environmental Studies, Zurich University, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Ludwig Institute for Cancer Research, Université Catholique de Louvain = Catholic University of Louvain (UCL), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hôpital Privé d'Antony, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris Cité (UPCité), and ANR-18-IBHU-0002,PRISM,PRecISion Medicine Institute in oncology(2018)
- Subjects
[SDV]Life Sciences [q-bio] ,Immunology ,Alpha interferon ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,[MATH.MATH-ST]Mathematics [math]/Statistics [math.ST] ,Tumor Cells, Cultured ,Humans ,Immunologic Factors ,Longitudinal Studies ,Prospective Studies ,Progenitor cell ,QA ,Gene ,030304 developmental biology ,Thrombopoietin receptor ,0303 health sciences ,Myeloproliferative Disorders ,biology ,Interferon-alpha ,Cell Biology ,Hematology ,Janus Kinase 2 ,Hematopoietic Stem Cells ,3. Good health ,Haematopoiesis ,030220 oncology & carcinogenesis ,Molecular Response ,Mutation ,biology.protein ,Cancer research ,Stem cell ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,Calreticulin ,Receptors, Thrombopoietin - Abstract
Classical BCR-ABL–negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon α (IFNα) has demonstrated some efficacy in inducing molecular remission in MPNs. To determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in patients with MPN 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 the clonal architecture of early and late hematopoietic progenitors (84 845 measurements) and the global variant allele frequency in mature cells (409 measurements) several times per year. Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSCs. Our data support the hypothesis that IFNα targets JAK2V617F HSCs by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSCs and increases with high IFNα dose in heterozygous JAK2V617F HSCs. We also found that the molecular responses of CALRm HSCs to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and a high dose of IFNα correlates with worse outcomes. 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 dose.
- Published
- 2021