Synergism 1 between RUNX1 and PHF6 mutations in leukemogenesis [scRNAseq]

RUNX family transcription factor 1 (RUNX1) mutated acute myeloid leukemia (AML) has now been formally classified as AML with myelodysplasia-related gene mutations, and considered to predict adverse prognosis. In addition, mutations of RUNX1 and plant homeodomain finger gene 6 (PHF6) frequently co-occurred and conferred particularly adverse clinical outcomes. Becasue the pathological effects of these combined mutations remained understudied, we sought to address this topic through genetically modified mouse models. We found that Phf6 knockout and RUNX1 double-mutated bone marrow (BM) cells displayed significantly higher engraftment capacity, and recipient mice transplanted with double-mutated BM cells developed AML with significantly shortened survival. We also discovered that the multipotent progenitors (MPPs) were the main cell subpopulation responsible for double-mutated BM cell-induced leukemia. Our findings highlighted the synergistic leukemogenic potential of Phf6 and RUNX1 mutations in vivo, and provided evidence for possible underlying molecular mechanisms. Overall design: We transduced vectors carrying the RUNX1-S291fs mutation (with GFP) into wild-type (WT) and Phf6 knockout (KO) mouse BM cells, and then sorted GFP+ cells, which were transplanted into recipient mice. Eight-week post-transplant, we sorted for GFP+Lin- cells from recipient mice bone marrow for scRNA-seq.