The Transcriptomic Landscape and Directed Chemical Interrogation of MLL-rearranged Acute Myeloid Leukemias

Nat Genet. 2015 Sep;47(9):1030-7. doi: 10.1038/ng.3371. Epub 2015 Aug 3.

Abstract

Using next-generation sequencing of primary acute myeloid leukemia (AML) specimens, we identified to our knowledge the first unifying genetic network common to the two subgroups of KMT2A (MLL)-rearranged leukemia, namely having MLL fusions or partial tandem duplications. Within this network, we experimentally confirmed upregulation of the gene with the most subtype-specific increase in expression, LOC100289656, and identified cryptic MLL fusions, including a new MLL-ENAH fusion. We also identified a subset of MLL fusion specimens carrying mutations in SPI1 accompanied by inactivation of its transcriptional network, as well as frequent RAS pathway mutations, which sensitized the leukemias to synthetic lethal interactions between MEK and receptor tyrosine kinase inhibitors. This transcriptomics-based characterization and chemical interrogation of human MLL-rearranged AML was a valuable approach for identifying complementary features that define this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Case-Control Studies
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Leukemic*
  • Gene Regulatory Networks
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Neoplasm Transplantation
  • Oncogene Proteins, Fusion / genetics
  • Transcriptome*
  • Translocation, Genetic
  • ras Proteins / genetics

Substances

  • Antineoplastic Agents
  • KMT2A protein, human
  • Oncogene Proteins, Fusion
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • ras Proteins