De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.

ABSTRACT: Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3 ^ITD , FLT3 ^N676K , and NRAS ^G12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3 ^N676K mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells. We identify acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 in KMT2A-MLLT3 leukemia cells that favored clonal expansion. During clonal evolution, we observe serial genetic changes at

SUBMITTER: Hyrenius-Wittsten A 

PROVIDER: S-EPMC5932012 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature