title: SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment.
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.
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London SE5 9NU, UK.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Mian
authors.affiliation: Human Normal and Malignant Haematopoiesis Stem Cells and Their Microenvironment Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rouault-Pierre
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London SE5 9NU, UK.|Department of Haematology, King's College Hospital, London SE5 9RS, UK.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Smith
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London SE5 9NU, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seidl
authors.affiliation: Human Normal and Malignant Haematopoiesis Stem Cells and Their Microenvironment Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Pizzitola
authors.affiliation: Department of Haematology, King's College Hospital, London SE5 9RS, UK.
authors.forename: Aytug
authors.initials: A
authors.lastname: Kizilors
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London SE5 9NU, UK.|Department of Haematology, King's College Hospital, London SE5 9RS, UK.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Kulasekararaj
authors.affiliation: Human Normal and Malignant Haematopoiesis Stem Cells and Their Microenvironment Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London SE5 9NU, UK.|Department of Haematology, King's College Hospital, London SE5 9RS, UK.
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D000368:Aged; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000235:genetics*; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D055815:Young Adult
chemical_list: D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human