衰老促进了携带克隆性造血干细胞突变的造血干细胞（HSC）的扩增，从而导致髓系恶性肿瘤的发展，例如骨髓增生性肿瘤（MPNs）。虽然合作突变可以引起HSC的转化，但目前还不清楚不同的骨髓HSC微环境是否会影响携带相同致癌驱动基因的HSC的生长和治疗反应。在这里，我们发现MPN亚型中的HSC具有不同的骨髓微环境。JAK-STAT信号传导差异调节了CDC42依赖的HSC极性、微环境相互作用和突变细胞扩增。非对称HSC分布导致了骨髓微环境的差异性重塑：多红细胞增多症中的窦腔扩张和原发性血小板增多症中的骨内微环境扩展。在过早老化的骨髓微环境中，MPN的发展加速，这表明特殊的微环境可以调节突变细胞的扩增。最后，不同的HSC-微环境相互作用决定了对JAK抑制剂的不同临床反应。因此，HSC-微环境相互作用影响了携带相同克隆性造血性致癌基因的细胞扩增速率和治疗反应。© 2023. 作者。

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.© 2023. The Author(s).