Type 1 interferon perturbates clonal competition by reshaping human blood development.

IF 25.5 1区生物学 Q1 GENETICS & HEREDITY

Nature genetics Pub Date : 2026-09-15 DOI:10.1038/s41588-026-02751-3

Chhiring Lama, Danielle Isakov, Shira Rosenberg, Miguel Quijada-Álamo, Mirca S Saurty-Seerunghen, Sara Moein, Mathis Nozais, Tsega-Ab Abera, Olivia Sakaguchi, Mansi Totwani, Grace Freed, Leila Zaydon, Chi-Lam Poon, Neelang Parghi, Andrea Kubas-Meyer, Amy X Xie, Mohamed Omar, Daniel Choi, Franco Castillo-Tokumori, Ghaith Abu-Zeinah, Alicia Dillard, Saravanan Ganesan, Nathaniel D Omans, Neville Dusaj, Paulina Chamely, Eleni Mimitou, Peter Smibert, Heidi E Kosiorek, Amylou C Dueck, Rona Weinberg, Ronan Chaligne, Bridget Marcellino, Luigi Marchionni, Sanjay Patel, Paul Simonson, Dan A Landau, Elvin Wagenblast, Ronald Hoffman, Anna S Nam

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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.

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1型干扰素通过重塑人类血液发育扰乱克隆竞争。

炎症加速造血干细胞（hsc）在克隆造血和髓系肿瘤中的进化动力学。我们研究了骨髓增殖性肿瘤患者的造血干细胞、祖细胞和免疫细胞在基线和干扰素-α (IFNα)治疗后的变化，干扰素-α是唯一消耗突变干细胞的治疗方法。我们采用单细胞多组学方法，从分化、转录组、免疫表型和染色质可及性方面区分IFNα对突变干细胞和混合野生型造血干细胞的影响。IFNα同时激活造血干细胞进入两种极化状态：与抗炎状态相关的淋巴样祖细胞扩张和源自造血干细胞的炎性髓样祖细胞状态。增强的淋巴细胞分化平衡了典型的骨髓增殖性肿瘤诱导的髓细胞偏倚，与正常血细胞计数相关。体细胞突变改变了IFNα对HSC分化和细胞周期进入率的影响。IFNα暴露下的克隆适应性是由于CALR-或jak2突变干细胞对分化为炎性髓系祖细胞的抵抗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution