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

  • Nat Cancer. 2023 Aug 7. doi: 10.1038/s43018-023-00607-x.
Elodie Grockowiak  1  2  3 ,  Claudia Korn  1  2  3 ,  Justyna Rak  1  2  3 ,  Veronika Lysenko  4 ,  Adrien Hallou  3  5  6  7 ,  Francesca M Panvini  1  2  3 ,  Matthew Williams  2  3 ,  Claire Fielding  1  2  3 ,  Zijian Fang  1  2  3 ,  Eman Khatib-Massalha  1  2  3 ,  Andrés García-García  1  2  3 ,  Juan Li  2  3 ,  Reema A Khorshed  8  9 ,  Sara González-Antón  8  9 ,  E Joanna Baxter  1  2 ,  Anjali Kusumbe  10 ,  Bridget S Wilkins  11 ,  Anna Green  11 ,  Benjamin D Simons  3  5  6  7 ,  Claire N Harrison  11 ,  Anthony R Green  2  3 ,  Cristina Lo Celso  #  8  9 ,  Alexandre P A Theocharides  #  4 ,  Simón Méndez-Ferrer  12  13  14
Affiliations
  • 1. National Health Service Blood and Transplant, Cambridge, UK.
  • 2. Department of Haematology, University of Cambridge, Cambridge, UK.
  • 3. Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK.
  • 4. Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.
  • 5. Wellcome Trust-CRUK Gurdon Institute, University of Cambridge, Cambridge, UK.
  • 6. Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK.
  • 7. Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK.
  • 8. Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, UK.
  • 9. The Sir Francis Crick Institute, London, UK.
  • 10. The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
  • 11. Guy's and Saint Thomas' NHS Foundation Trust, London, UK.
  • 12. National Health Service Blood and Transplant, Cambridge, UK. [email protected].
  • 13. Department of Haematology, University of Cambridge, Cambridge, UK. [email protected].
  • 14. Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, UK. [email protected].
  • # Contributed equally.
PMID: 37550517 DOI: 10.1038/s43018-023-00607-x
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.

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