title: Epigenetic regulation of GATA2 and its impact on normal karyotype acute myeloid leukemia.
abstract: The GATA2 gene encodes a zinc-finger transcription factor that acts as a master regulator of normal hematopoiesis. Mutations in GATA2 have been implicated in the development of myelodysplastic syndrome and acute myeloid leukemia (AML). Using RNA sequencing we now report that GATA2 is either mutated with a functional consequence, or expressed at low levels in the majority of normal karyotype AML (NK-AML). We also show that low-GATA2-expressing specimens (GATA2(low)) exhibit allele-specific expression (ASE) (skewing) in more than half of AML patients examined. We demonstrate that the hypermethylation of the silenced allele can be reversed by exposure to demethylating agents, which also restores biallelic expression of GATA2. We show that GATA2(low) AML lack the prototypical R882 mutation in DNMT3A frequently observed in NK-AML patients and that The Cancer Genome Atlas AML specimens with DNMT3A R882 mutations are characterized by CpG hypomethylation of GATA2. Finally, we validate that several known missense single-nucleotide polymorphisms in GATA2 are actually loss-of-function variants, which, when combined with ASE, represent the equivalent of homozygous GATA2 mutations. From a broader perspective, this work suggests for the first time that determinants of ASE likely have a key role in human leukemia.
authors: 1] Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Québec, Canada [2] Laboratory for high-throughput genomics, Montreal, Québec, Canada [3] INRA, UMR1083, Sciences Pour l'Oenologie, Montpellier, France.
authors: M
authors: M
authors: Celton
authors: 1] Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Québec, Canada [2] Laboratory for high-throughput genomics, Montreal, Québec, Canada.
authors: A
authors: A
authors: Forest
authors: 1] Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Québec, Canada [2] Laboratory for high-throughput genomics, Montreal, Québec, Canada.
authors: G
authors: G
authors: Gosse
authors: 1] Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Québec, Canada [2] Laboratory for Functional and Structural Bioinformatics, Montreal, Québec, Canada.
authors: S
authors: S
authors: Lemieux
authors: 1] Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Québec, Canada [2] Leukemia Cell Bank of Quebec and Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Québec, Canada.
authors: J
authors: J
authors: Hebert
authors: 1] Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Québec, Canada [2] Leukemia Cell Bank of Quebec and Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Québec, Canada [3] Laboratory for Molecular Genetics of Stem Cells, Montreal, Québec, Canada.
authors: G
authors: G
authors: Sauvageau
authors: 1] Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, Québec, Canada [2] Laboratory for high-throughput genomics, Montreal, Québec, Canada.
authors: B T
authors: BT
authors: Wilhelm
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D050989:GATA2 Transcription Factor / Q000235:genetics*; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: C000717967:DNMT3A protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A