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Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms.

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posted on 2023-09-01, 10:27 authored by Elodie Grockowiak, Claudia Korn, Justyna Rak, Veronika Lysenko, Adrien Hallou, Francesca M Panvini, Matthew Williams, Claire Fielding, Zijian Fang, Eman Khatib-Massalha, Andrés García-García, Juan Li, Reema A Khorshed, Sara González-Antón, E Joanna Baxter, Anjali Kusumbe, Bridget S Wilkins, Anna Green, Benjamin D Simons, Claire N Harrison, Anthony R Green, Cristina Lo Celso, Alexandre PA Theocharides, Simón Méndez-Ferrer
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.

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