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

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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 the Kras G12D locus, consistent with a strong selective advantage of additional Kras G12D . KMT2A-MLLT3 leukemias with signaling mutations enforce Myc and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlight the importance of activated signaling as a contributing driver.


  • Helena Sturesson
  • Michael P. Walsh
  • Guangchun Song
  • Jian Liu
  • Cristian Garcia-Ruiz
  • Stephanie Nance
  • Pankaj Gupta
  • Jinghui Zhang
  • James R. Downing
  • Tanja A. Gruber
  • Jing Ma
External organisations
  • St Jude Children´s Research Hospital, Memphis
  • Skåne University Hospital
  • Lund University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology
  • Medical Genetics
Original languageEnglish
Article number1770
JournalNature Communications
Issue number1
Publication statusPublished - 2018 Dec 1
Publication categoryResearch