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Mutations in the RNA splicing geneSF3B1are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin ofSF3B1mutations 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 inSF3B1in 39 of 40 cases (97.5%), combined withTET2andDNMT3Ain 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 (SF3B1mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence forSF3B1mutations targeting lymphomyeloid HSCs and compatible with mutatedSF3B1negatively 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 theSF3B1mutated clone. Upon transplantation into immune-deficient mice,SF3B1mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin ofSF3B1mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploringSF3B1mutated MDS-RS.

Original publication




Journal article



Publication Date





881 - 890


Aged, Aged, 80 and over, Animals, Cell Differentiation, Female, Hematopoietic Stem Cells, Humans, Lymphocytes, Male, Mice, Middle Aged, Mutation, Myelodysplastic Syndromes, Myeloid Cells, Phosphoproteins, RNA Splicing Factors, Spliceosomes