Nature cancer · 2023
Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Grockowiak Elodie, Korn Claudia, Rak Justyna, Lysenko Veronika, Hallou Adrien, Panvini Francesca M, Williams Matthew, Fielding Claire, Fang Zijian, Khatib-Massalha Eman, García-García Andrés, Li Juan, Khorshed Reema A, González-Antón Sara, Baxter E Joanna, Kusumbe Anjali, Wilkins Bridget S, Green Anna, Simons Benjamin D, Harrison Claire N, Green Anthony R, Lo Celso Cristina, Theocharides Alexandre P A, Méndez-Ferrer Simón
Аннотация
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.