JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality
Open accessAbstract
We studied a subset of hematopoietic stem cells (HSCs) that are defined by elevated expression of CD41 (CD41hi) and showed bias for differentiation toward megakaryocytes (Mks). Mouse models of myeloproliferative neoplasms (MPNs) expressing JAK2-V617F (VF) displayed increased frequencies and percentages of the CD41hi vs CD41lo HSCs compared with wild-type controls. An increase in CD41hi HSCs that correlated with JAK2-V617F mutant allele burden was also found in bone marrow from patients with MPN. CD41hi HSCs produced a higher number of Mk-colonies of HSCs in single-cell cultures in vitro, but showed reduced long-term reconstitution potential compared with CD41lo HSCs in competitive transplantations in vivo. RNA expression profiling showed an upregulated cell cycle, Myc, and oxidative phosphorylation gene signatures in CD41hi HSCs, whereas CD41lo HSCs showed higher gene expression of interferon and the JAK/STAT and TNFα/NFκB signaling pathways. Higher cell cycle activity and elevated levels of reactive oxygen species were confirmed in CD41hi HSCs by flow cytometry. Expression of Epcr, a marker for quiescent HSCs inversely correlated with expression of CD41 in mice, but did not show such reciprocal expression pattern in patients with MPN. Treatment with interferon-α further increased the frequency and percentage of CD41hi HSCs and reduced the number of JAK2-V617F+ HSCs in mice and patients with MPN. The shift toward the CD41hi subset of HSCs by interferon-α provides a possible mechanism of how interferon-α preferentially targets the JAK2 mutant clone.
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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 [12]
IFNa remains a highly effective therapy for MPN, frequently resulting in normalization of patients' blood counts and even molecular response.
“IFNa remains a highly effective therapy for MPN, frequently resulting in the normalization of the patients' blood counts and even molecular response (i.e. reduction in variant allele frequencies), with evidence suggesting that IFNa may deplete clonal stem cells via induction of HSCs into cell cycle entry and exhaustion 12,18 .”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [12]
IFNa may deplete clonal stem cells via induction of HSCs into cell cycle entry and exhaustion.
“IFNa remains a highly effective therapy for MPN, frequently resulting in the normalization of the patients' blood counts and even molecular response (i.e. reduction in variant allele frequencies), with evidence suggesting that IFNa may deplete clonal stem cells via induction of HSCs into cell cycle entry and exhaustion 12,18 .”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [12]
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Type 1 interferon perturbates clonal competition by reshaping human blood development
Lama, C., Isakov, D., Rosenberg, S., Quijada-Álamo, M., Saurty-Seerunghen, M. S., Moein, S., Nozais, M., Abera, T.-A., Sakaguchi, O., Totwani, M., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02751-3 · Cited by 3 · see citing works
Interferon-α directs hematopoietic stem cells toward competing fates
Rodriguez-Meira, A. (2026) · Nature Genetics · doi:10.1038/s41588-026-02797-3
- Authors
- Rao, T. N., Hansen, N., Stetka, J., Luque Paz, D., Kalmer, M., Hilfiker, J., Endele, M., Ahmed, N., Kubovcakova, L., Rybarikova, M., Hao-Shen, H., Geier, F., Beisel, C., Dirnhofer, S., Schroeder, T., Brümmendorf, T. H., Wolf, D., Koschmieder, S., & Skoda, R. C.
- Affiliations
- University of Basel (CH)
- Department of Biomedicine, Experimental Hematology, University Hospital Basel–University of Basel, Basel, Switzerland;
- RWTH Aachen University (DE)
- ETH Zurich (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- University Hospital of Basel (CH)
- Innsbruck Medical University (AT)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2021-04-22
- Volume
- 137
- Issue
- 16
- Pages
- 2139-2151
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC8103999
- OpenAlex
- W3133520808
- Cited by
- 72
- References
- 4
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 9 · 2023: 7 · 2022: 12 · 2021: 13
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Hematology Association (TRTH159)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (147016, 166613)
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- JAK2 V617F mutation, interferon-alpha, hematopoietic stem cells, CD41, megakaryopoiesis, myeloproliferative neoplasms, endothelial protein C receptor, reactive oxygen species, cell cycle, JAK/STAT signaling, interferon gene expression, mutant allele burden, stem cell quiescence
- MeSH terms
- Animals, Hematopoietic Stem Cells, Humans, Megakaryocytes, Mice, Transgenic, Myeloproliferative Disorders, Interferon-alpha, Point Mutation, Platelet Membrane Glycoprotein IIb, Mice, Janus Kinase 2, Gene Knock-In Techniques
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