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

Autor:	Mosca M; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris-Saclay, Gif-sur-Yvette, France.; Laboratoire d'Excellence GR-Ex, Paris, France., Hermange G; Université Paris-Saclay, CentraleSupélec, Laboratory MICS (Laboratory of Applied Mathematics and Computer Science), Gif-sur-Yvette, France., Tisserand A; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Laboratoire d'Excellence GR-Ex, Paris, France.; Université de Paris, Paris, France., Noble R; Department of Biosciences and Engineering, ETH Zurich, Basel, Switzerland.; Institut des Sciences de l'Evolution, University of Montpellier, Montpellier, France.; Institute of Evolutionary Biology and Environmental Studies (IEU), University of Zurich, Zurich, Switzerland.; University of London, London, United Kingdom., Marzac C; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris-Saclay, Gif-sur-Yvette, France.; Laboratoire d'Immuno-Hématologie, Gustave Roussy, Villejuif, France., Marty C; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris-Saclay, Gif-sur-Yvette, France.; Laboratoire d'Excellence GR-Ex, Paris, France., Le Sueur C; Department of Biosciences and Engineering, ETH Zurich, Basel, Switzerland., Campario H; Laboratoire d'Hématologie, CHU Dijon, Dijon, France., Vertenoeil G; Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels, Belgium., El-Khoury M; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Laboratoire d'Excellence GR-Ex, Paris, France., Catelain C; UMS AMMICa-Plateforme Imagerie et Cytométries, Gustave Roussy, Villejuif, France., Rameau P; UMS AMMICa-Plateforme Imagerie et Cytométries, Gustave Roussy, Villejuif, France., Gella C; Laboratoire d'Immuno-Hématologie, Gustave Roussy, Villejuif, France., Lenglet J; Hôpital Privé d'Antony, Antony, France., Casadevall N; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Assistance Publique des Hôpitaux de Paris, Laboratoire d'Hématologie, Hôpital Saint-Antoine, Paris, France., Favier R; Assistance Publique des Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpital d'Enfants Armand-Trousseau, Paris, France., Solary E; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Département d'Hématologie, Gustave Roussy, Villejuif, France.; Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France., Cassinat B; Université de Paris, INSERM UMR-S 1131, Institut de Recherche Saint-Louis (IRSL), Hôpital Saint-Louis, Paris, France.; Assistance Publique des Hôpitaux de Paris, Laboratoire de Biologie Cellulaire., Kiladjian JJ; Université de Paris, INSERM UMR-S 1131, Institut de Recherche Saint-Louis (IRSL), Hôpital Saint-Louis, Paris, France.; Assistance Publique des Hôpitaux de Paris, Centre d'Investigations Cliniques, Hôpital Saint-Louis, Paris, France., Constantinescu SN; Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels, Belgium., Pasquier F; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris-Saclay, Gif-sur-Yvette, France.; Département d'Hématologie, Gustave Roussy, Villejuif, France., Hochberg ME; Institut des Sciences de l'Evolution, University of Montpellier, Montpellier, France.; Santa Fe Institute, Santa Fe, NM., Raslova H; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris-Saclay, Gif-sur-Yvette, France., Villeval JL; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris-Saclay, Gif-sur-Yvette, France., Girodon F; Laboratoire d'Hématologie, CHU Dijon, Dijon, France.; INSERM, UMR 866, Centre de Recherche, Dijon, France; and., Vainchenker W; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris-Saclay, Gif-sur-Yvette, France.; Laboratoire d'Excellence GR-Ex, Paris, France.; Assistance Publique des Hôpitaux de Paris, Service d'Immunopathologie Clinique, Polyclinique d'Hématologie, Hôpital Saint-Louis, Paris, France., Cournède PH; Université Paris-Saclay, CentraleSupélec, Laboratory MICS (Laboratory of Applied Mathematics and Computer Science), Gif-sur-Yvette, France., Plo I; INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris-Saclay, Gif-sur-Yvette, France.; Laboratoire d'Excellence GR-Ex, Paris, France.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Dec 02; Vol. 138 (22), pp. 2231-2243.
DOI:	10.1182/blood.2021010986
Abstrakt:	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. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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