Journal
NATURE GENETICS
Volume 47, Issue 9, Pages 1030-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3371
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Funding
- Genome Canada
- Genome Quebec
- Amorchem
- Canadian Cancer Society Research Institute (CCSRI)
- Industrielle-Alliance (Universite de Montreal)
- Canada Research Chair program
- Cancer Research Network of the Fonds de Recherche du Quebec-Sante
- Canada Foundation for Innovation (CFI)
- NanoQuebec
- RMGA
- Fonds de Recherche du Quebec-Nature et Technologies (FRQ-NT)
- Hopital Maisonneuve-Rosemont Foundation
- Cole Foundation
- Human Frontier Science Program
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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.
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