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

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Grockowiak, Elodie 
Korn, Claudia 
Rak, Justyna 

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.

Description

Keywords

Humans, Aged, Myeloproliferative Disorders, Bone Marrow, Hematopoietic Stem Cells, Bone and Bones, Neoplasms, Tumor Microenvironment

Journal Title

Nat Cancer

Conference Name

Journal ISSN

2662-1347
2662-1347

Volume Title

4

Publisher

Springer Science and Business Media LLC
Sponsorship
European Research Council (648765)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (C61367/A26670)
MRC (MR/V005421/1)
Medical Research Council (MC_PC_17230)
Wellcome Trust (203151/A/16/Z)