2. Academic Validation
  3. 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

  • 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

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.

Figures
Products