Type 1 interferon perturbates clonal competition by reshaping human blood development
Inflammation accelerates evolutionary dynamics of hematopoietic stem cells (HSCs) in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasms at baseline and following interferon-α (IFNα) treatment, the only therapy to deplete mutated stem cells. We deployed single-cell multiomics methods that distinguish the IFNα effects on mutated stem cells from the admixed wild-type HSCs, with respect to their differentiation, transcriptomes, immunophenotypes and chromatin accessibility. IFNα simultaneously activated HSCs into two polarized states: a lymphoid progenitor expansion associated with an anti-inflammatory state and an inflammatory myeloid progenitor state derived from HSCs. The augmented lymphoid differentiation balanced the typical myeloproliferative-neoplasm-induced myeloid bias, associated with normalized blood counts. Somatic mutations modified the effects of IFNα on HSC differentiation and cell cycle entry rates. Clonal fitness upon IFNα exposure was due to resistance of CALR- or JAK2-mutated stem cells to differentiate into inflammatory myeloid progenitors. Single-cell multiomics of blood stem cells from patients with myeloproliferative neoplasms revealed that interferon-α normalizes blood counts by augmenting lymphoid differentiation and modulates clonal dynamics via inflammatory myeloid differentiation
Authors
- Ronald Hoffman (ORCID: https://orcid.org/0000-0001-6564-6732)
- Amy Xie (ORCID: https://orcid.org/0000-0002-1441-7849)
- Eleni P. Mimitou (ORCID: https://orcid.org/0000-0001-9737-6394)
- Dan A. Landau
- Shira Rosenberg (ORCID: https://orcid.org/0000-0002-4760-0746)
- Heidi Kosiorek (ORCID: https://orcid.org/0000-0002-4651-9516)
- Peter Smibert (ORCID: https://orcid.org/0000-0003-0772-1647)
- Sanjay S. Patel (ORCID: https://orcid.org/0000-0002-7813-4573)
- Mathis Nozais (ORCID: https://orcid.org/0000-0001-8114-904X)
- Andrea Kubas-Meyer
- Sara Moein
- Nathaniel D. Omans (ORCID: https://orcid.org/0000-0003-0604-1893)
- Elvin Wagenblast (ORCID: https://orcid.org/0000-0002-0709-2759)
- Chhiring Lama
- Miguel Quijada‐Álamo (ORCID: https://orcid.org/0000-0002-4831-4565)
- Saravanan Ganesan (ORCID: https://orcid.org/0000-0002-5773-1715)
- Ghaith Abu‐Zeinah (ORCID: https://orcid.org/0000-0002-1881-3670)
- Franco Castillo Tokumori (ORCID: https://orcid.org/0000-0002-2245-4068)
- Luigi Marchionni (ORCID: https://orcid.org/0000-0002-7336-8071)
- Ronan Chaligné (ORCID: https://orcid.org/0000-0003-4332-3291)
- Chi-Lam Poon (ORCID: https://orcid.org/0000-0001-6298-7099)
- Amylou C. Dueck (ORCID: https://orcid.org/0000-0002-9912-1085)
- Anna S. Nam (ORCID: https://orcid.org/0000-0003-4192-8916)
- Olivia Sakaguchi
- Bridget Marcellino
- Mansi Totwani (ORCID: https://orcid.org/0009-0006-4912-3388)
- Tsega-Ab Abera
- Paul Simonson
- Daniel Choi
- Alicia Dillard
- Paulina Chamely
- Grace Freed
- Danielle Isakov
- Neelang Parghi
- Mirca S. Saurty-Seerunghen
- Rona Weinberg
- Leila Zaydon
- Neville Dusaj
- Mohamed Omar
Institutions
- Cedars-Sinai Medical Center (US)
- Mayo Clinic (US)
- Memorial Sloan Kettering Cancer Center (US)
- New York Blood Center (US)
- Cornell University (US)
- Immunai (United States) (US)
- Tri-Institutional PhD Program in Chemical Biology (US)
- Mayo Clinic in Arizona (US)
- New York Genome Center (US)
- Weill Cornell Medicine (US)
- Rockefeller University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2026-09-15
- DOI
- https://doi.org/10.1038/s41588-026-02751-3
- Primary Topic
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00