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Cited by 57Myeloproliferative Neoplasms: Diagnosis and TreatmentAcute Myeloid Leukemia ResearchPlatelet Disorders and Treatments

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

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Mosca, Matthieu, Hermange, Gurvan, Tisserand, Amandine, Noble, Robert, Marzac, Christophe, Marty, Caroline, Le Sueur, Cécile, Campario, Hugo +20 more·2021·Blood
DOI 10.1182/blood.2021010986PMC PMC8641097
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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.

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  • These cytokines display overlapping features, such as inducing cell cycle entry of HSCs and their differentiation, frequently toward the granulo-monocytic lineage.

    “These cytokines display overlapping features, such as inducing cell cycle entry of HSCs and their differentiation, frequently toward the granulo-monocytic lineage 1,4-6,12-15 .”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [13]

    The Discussion (page not available) says IFNα treatment promotes exit from quiescence and differentiation of mutated HSCs into progenitors, supporting those features for IFNα. It does not establish that differentiation is frequently toward the granulo-monocytic lineage, and its findings concern mutated HSCs in myeloproliferative neoplasms rather than HSCs generally. (LLM, conf=0.86)

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Research works printed but not linked: 31

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Authors
Mosca, M., Hermange, G., Tisserand, A., Noble, R., Marzac, C., Marty, C., Le Sueur, C., Campario, H., Vertenoeil, G., El-Khoury, M., Catelain, C., Rameau, P., Gella, C., Lenglet, J., Casadevall, N., Favier, R., Solary, E., Cassinat, B., Kiladjian, J.-J., Constantinescu, S. N., Pasquier, F., Hochberg, M. E., Raslova, H., Villeval, J.-L., Girodon, F., Vainchenker, W., Cournède, P.-H., & Plo, I.
Affiliations
  • Inserm (FR)
  • Supélec (FR)
  • University of London (GB)
  • Department of Biosciences and Engineering, ETH Zurich, Basel, Switzerland;
  • CHU Dijon Bourgogne (FR)
  • Ludwig Cancer Research (BE)
  • Institut Gustave Roussy (FR)
  • Hôpital Privé d’Antony, Antony, France;
  • Hôpital Armand-Trousseau (FR)
  • INSERM, Unité Mixte de Recherche (UMR) 1287, Gustave Roussy, Villejuif, France;
  • Santa Fe Institute (US)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2021-12-02
Volume
138
Issue
22
Pages
2231-2243
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2021010986
PMC
PMC8641097
OpenAlex
W3195336015
Cited by
57
References
4
Citations by year
2026: 14 · 2025: 6 · 2024: 13 · 2023: 12 · 2022: 10 · 2021: 2
FWCI
5.19
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • City Research Online (City University London) (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
Funders
  • MPN Research Foundation
  • Agence Nationale de la Recherche (ANR-18-IBHU-0002, ANR18)
  • Fonds De La Recherche Scientifique - FNRS
  • Ligue Contre le Cancer
  • Institut National Du Cancer
  • Institut Gustave-Roussy
  • Fondation Gustave Roussy
  • Société Française d'Hématologie
  • National Institutes of Health
  • National Cancer Institute (U54CA217376)
Topics
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Keywords
myeloproliferative neoplasms, interferon-alpha, hematopoietic stem cells, JAK2 V617F mutation, CALR mutation, MPL mutation, clonal architecture, variant allele frequency, HSC quiescence, HSC differentiation, molecular remission, interferon dose, HSC exhaustion, mathematical modeling, Bayesian inference
MeSH terms
Hematopoietic Stem Cells, Humans, Immunologic Factors, Longitudinal Studies, Mutation, Myeloproliferative Disorders, Prospective Studies, Tumor Cells, Cultured, Interferon-alpha, Calreticulin, Janus Kinase 2, Receptors, Thrombopoietin

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