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

Nat Commun. 2018 May 2;9(1):1770. doi: 10.1038/s41467-018-04180-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Clonal Evolution*
  • Gene Expression Regulation, Leukemic
  • Gene Rearrangement*
  • Histone-Lysine N-Methyltransferase / genetics*
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / pathology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation*
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Oncogene Proteins, Fusion / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics


  • Oncogene Proteins, Fusion
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)