Identification of functional cooperative mutations of SETD2 in human acute leukemia

Nat Genet. 2014 Mar;46(3):287-93. doi: 10.1038/ng.2894. Epub 2014 Feb 9.


Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Child, Preschool
  • Chromosome Aberrations
  • Diseases in Twins / genetics
  • Epigenesis, Genetic
  • Female
  • Gene Fusion
  • Genes, Tumor Suppressor
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Leukemia / genetics*
  • Leukemia, Monocytic, Acute / genetics
  • Mutation*
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Nuclear Proteins / genetics
  • Point Mutation
  • Translocation, Genetic
  • Twins, Monozygotic


  • Adaptor Proteins, Signal Transducing
  • DCAF6 protein, human
  • KMT2A protein, human
  • Nuclear Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Set2 protein, human

Associated data

  • SRA/SRA123673