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Blood. 2017 Aug 17;130(7):881-890. doi: 10.1182/blood-2017-03-776070. Epub 2017 Jun 20.

SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells.

Author information

1
Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
2
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
3
Memorial Sloan Kettering Cancer Center, New York, NY; and.
4
Division of Hematopathology, Department of Pathology, Karolinska University Hospital, Solna, Sweden.

Abstract

Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal (SF3B1 mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for SF3B1 mutations targeting lymphomyeloid HSCs and compatible with mutated SF3B1 negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the SF3B1 mutated clone. Upon transplantation into immune-deficient mice, SF3B1 mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of SF3B1 mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring SF3B1 mutated MDS-RS.

PMID:
28634182
PMCID:
PMC5572789
DOI:
10.1182/blood-2017-03-776070
[Indexed for MEDLINE]
Free PMC Article

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