Patient Derived Neomorphic SEPTIN6 Mutations Induce Hematopoietic Stem Cell Senescence Underlying Congenital Neutropenia and Myelodysplasia

We previously described two pediatric patients harboring SEPT6 germline mutations (GM1:SEPT6 c.1282T>C and GM2:SEPT6 c.1282T>A) presenting with congenital neutropenia associated with the development of myelodysplastic syndrome. In one patient, an additional somatic mutation (SM:SEPT6 c.43C>T) was detected at a low allelic fraction in the BM.

Here, we describe the consequences of these mutations on hematopoiesis. Transgenic expression or gene editing of GM1 or GM2 in human CD34+ cells led to enlarged, multinucleated cells associated with accelerated exhaustion and premature senescence of hematopoietic stem and progenitor cells (HSPCs). Senescence defects were associated with the upregulation of mTOR phosphorylation; and pharmacologic inhibition of the mTOR pathway resulted in rescue of senescence.