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

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Grockowiak, Elodie 
Korn, Claudia 
Rak, Justyna 

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.


Acknowledgements: We thank D. Bonnet, D. Passaro, A. Batsivari, H. Qian, L. Sandhow, R. C. Skoda, C. Nerlov, G. N. Enikolopov for the mouse models; N. Richoz and M. Clatworthy for access to intravital imaging; L. Arranz, C. L. F. de Castillejo, A. Rodríguez-Romera, C. Kapeni, E. Carrillo and other members of the S.M.-F group for assistance and discussions; A. Castillo Venzor, D. Pask, T. Hamilton (University of Cambridge) and the Central Biomedical Services & the Anne McLaren Building staff for support; and the Wellcome Trust-MRC Stem Cell Institute imaging core (D. Clements) and histopathology core (I. Pshenichnaya), the CIMR flow cytometry core (R. Schulte and G. Gondrys-Kotarba) and the Cambridge National Institute for Health and Care Research (NIHR) BRC Cell Phenotyping Hub for technical assistance. Samples were provided by the Cambridge Blood and Stem Cell Biobank, which is supported by the Cambridge NIHR Biomedical Research Centre, Wellcome Trust-Medical Research Council (MRC) Stem Cell Institute and the Cambridge Experimental Cancer Medicine Centre, UK. A.H. gratefully acknowledges the support of the University of Cambridge Herchel Smith Fund through a Herchel Smith Postdoctoral Research Fellowship and the support of Darwin College Cambridge through a Research Fellowship. A.H. and B.D.S. also acknowledge the support of the core funding to the Wellcome/Cancer Research UK Gurdon Institute (nos. 203144/Z/16/Z and C6946/A24843). Work in the A.R.G. laboratory was supported by Wellcome (no. RG74909), WBH Foundation (no. RG91681), Alborada Trust (no. RG109433) and Cancer Research UK (no. RG83389). This work was supported by core support grants from the Wellcome Trust (no. 203151/Z/16/Z) and the MRC to the Cambridge Stem Cell Institute, Marie Skłodowska-Curie Career Action H2020-MSCA-IF-2015-708411 to C.K., National Health Institute Blood and Transplant (UK), Horizon 2020 ERC-2014-CoG-648765, MRC-AMED grant no. MR/V005421/1 and a Programme Foundation Award (no. C61367/A26670) from Cancer Research UK to S.M.-F. This research was funded in whole, or in part, by the Wellcome Trust (no. 203151/Z/16/Z) and the UK Research and Innovation MRC (no. MC_PC_17230). For the purpose of open access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission.

Humans, Aged, Myeloproliferative Disorders, Bone Marrow, Hematopoietic Stem Cells, Bone and Bones, Neoplasms, Tumor Microenvironment
Journal Title
Nat Cancer
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Springer Science and Business Media LLC
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)