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SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment

Author

Listed:
  • Syed A. Mian

    (King’s College London School of Medicine)

  • Kevin Rouault-Pierre

    (Human Normal and Malignant Haematopoiesis Stem Cells and Their Microenvironment Laboratory, The Francis Crick Institute, Lincoln’s Inn Fields Laboratories)

  • Alexander E. Smith

    (King’s College London School of Medicine
    King’s College Hospital)

  • Thomas Seidl

    (King’s College London School of Medicine)

  • Irene Pizzitola

    (Human Normal and Malignant Haematopoiesis Stem Cells and Their Microenvironment Laboratory, The Francis Crick Institute, Lincoln’s Inn Fields Laboratories)

  • Aytug Kizilors

    (King’s College Hospital)

  • Austin G. Kulasekararaj

    (King’s College London School of Medicine
    King’s College Hospital)

  • Dominique Bonnet

    (Human Normal and Malignant Haematopoiesis Stem Cells and Their Microenvironment Laboratory, The Francis Crick Institute, Lincoln’s Inn Fields Laboratories)

  • Ghulam J. Mufti

    (King’s College London School of Medicine
    King’s College Hospital)

Abstract

Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34+CD38−CD45RA−CD90+CD49f+ HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target.

Suggested Citation

  • Syed A. Mian & Kevin Rouault-Pierre & Alexander E. Smith & Thomas Seidl & Irene Pizzitola & Aytug Kizilors & Austin G. Kulasekararaj & Dominique Bonnet & Ghulam J. Mufti, 2015. "SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10004
    DOI: 10.1038/ncomms10004
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    Cited by:

    1. Wei-Yu Lin & Sarah E. Fordham & Eric Hungate & Nicola J. Sunter & Claire Elstob & Yaobo Xu & Catherine Park & Anne Quante & Konstantin Strauch & Christian Gieger & Andrew Skol & Thahira Rahman & Lara , 2021. "Genome-wide association study identifies susceptibility loci for acute myeloid leukemia," Nature Communications, Nature, vol. 12(1), pages 1-10, December.

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