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

Abstract

Mutations in the RNA splicing gene <i>SF3B1</i> are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of <i>SF3B1</i> 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 <i>SF3B1</i> in 39 of 40 cases (97.5%), combined with <i>TET2</i> and <i>DNMT3A</i> 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 (<i>SF3B1</i> mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for <i>SF3B1</i> mutations targeting lymphomyeloid HSCs and compatible with mutated <i>SF3B1</i> 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 <i>SF3B1</i> mutated clone. Upon transplantation into immune-deficient mice, <i>SF3B1</i> 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 <i>SF3B1</i> mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring <i>SF3B1</i> mutated MDS-RS.