Nature genetics, 2015-09, Vol.47 (9), p.1030-1037
2015
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- Autor(en) / Beteiligte
- Titel
- The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias
- Ist Teil von
- Nature genetics, 2015-09, Vol.47 (9), p.1030-1037
- Ort / Verlag
- New York: Nature Publishing Group US
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Guy Sauvageau, Josée Hébert and colleagues analyze exomes and transcriptomes in MLL -rearranged acute myeloid leukemias. They find frequent RAS pathway mutations, which sensitize leukemias to MEK and receptor tyrosine kinase inhibitors. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1061-4036eISSN: 1546-1718DOI: 10.1038/ng.3371Titel-ID: cdi_proquest_miscellaneous_1708162069
- Format
- –
- Schlagworte
- 45/23, 45/91, 631/208/199, 631/208/212/1728, 631/208/212/2019, 692/699/1541/1990/283/1897, Agriculture, Animal Genetics and Genomics, Animals, Antineoplastic Agents - pharmacology, BCR-ABL tyrosine kinase inhibitors, Biomedicine, Cancer, Cancer Research, Case-Control Studies, Chromosomes, DNA sequencing, Drug Resistance, Neoplasm, Gene expression, Gene Expression Regulation, Leukemic, Gene Function, Gene Regulatory Networks, Genomes, Genomics, Histone-Lysine N-Methyltransferase - genetics, Human Genetics, Humans, Inactivation, Kinases, Leukemia, Leukemia, Myeloid, Acute - genetics, Leukemia, Myeloid, Acute - metabolism, Medical research, Mice, Inbred NOD, Mice, SCID, Morphology, Mutation, Myeloid-Lymphoid Leukemia Protein - genetics, Neoplasm Transplantation, Nucleotide sequencing, Oncogene Proteins, Fusion - genetics, ras Proteins - genetics, Studies, Supercomputers, Transcriptome, Translocation, Genetic