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

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

Nature cancer (2023-08-08)
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 P A Theocharides, Simón Méndez-Ferrer
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DAPI, for nucleic acid staining
Pricing and availability is not currently available.
Sigma-Aldrich
Anti-Cdc42 Antibody, from rabbit
Pricing and availability is not currently available.