Epigenetic regulation of GATA2 and its impact on normal karyotype acute myeloid leukemia

摘要: The GATA2 gene encodes a zinc-finger transcription factor that acts as master regulator of normal hematopoiesis. Mutations in have been implicated the development myelodysplastic syndrome and acute myeloid leukemia (AML). Using RNA sequencing we now report is either mutated with functional consequence, or expressed at low levels majority karyotype AML (NK-AML). We also show low-GATA2-expressing specimens (GATA2(low)) exhibit allele-specific expression (ASE) (skewing) more than half patients examined. demonstrate hypermethylation silenced allele can be reversed by exposure to demethylating agents, which restores biallelic GATA2. GATA2(low) lack prototypical R882 mutation DNMT3A frequently observed NK-AML Cancer Genome Atlas mutations are characterized CpG hypomethylation Finally, validate several known missense single-nucleotide polymorphisms actually loss-of-function variants, which, when combined ASE, represent equivalent homozygous mutations. From broader perspective, this work suggests for first time determinants ASE likely key role human leukemia.