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

The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias.

Author information

1
The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
2
Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
3
Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
4
Centre Hospitalier Universitaire de Québec, Centre de Recherche du Centre Hospitalier de l'Université Laval and Hôpital de l'Enfant-Jésus, Quebec City, Quebec, Canada.
5
Department of Medicine, Université Laval, Quebec City, Quebec, Canada.
6
Department of Computer Science and Operations Research, Université de Montréal, Montreal, Quebec, Canada.
7
Department of Chemistry, Université de Montréal, Montreal, Quebec, Canada.
8
Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.
9
Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
10
Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.

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.

PMID:
26237430
DOI:
10.1038/ng.3371
[Indexed for MEDLINE]
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