Type 1 interferon perturbates clonal competition by reshaping human blood development.
Key claim: IFNα reshapes human HSC differentiation into polarized anti-inflammatory lymphoid and inflammatory myeloid states, and CALR- or JAK2-mutated stem cells gain clonal fitness by resisting differentiation into inflammatory myeloid progenitors.
Abstract
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.
Why this matters
IFNα is a cornerstone disease-modifying therapy across PV, ET, and increasingly early MF, yet its selective pressure on mutant clones has lacked a unifying cellular mechanism. This work proposes that IFNα forces HSCs down a polarized lymphoid vs inflammatory-myeloid fate decision, and that CALR/JAK2-mutant stem cells are outcompeted specifically because they resist the inflammatory-myeloid arm — a cross-subtype mechanism that dovetails with the NK/TNF-α IFN effector axis and the broader inflammatory-network theme running through Ph-negative MPNs.