Demethylator phenotypes in acute myeloid leukemia
| Autor: | Charly R. Good, Andrew Kelly, Jozef Madzo, Jean Pierre J. Issa, Patricia Kropf, Priyanka Madireddi, Jaroslav Jelinek |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Cancer Research medicine.medical_specialty NPM1 Biology Article Epigenesis Genetic 03 medical and health sciences AML medicine Humans DNA (Cytosine-5-)-Methyltransferases DMP Epigenetics Aged Aged 80 and over DNA methylation CIMP Cytogenetics Nuclear Proteins demethylation Myeloid leukemia Hematology Middle Aged Prognosis Phenotype Up-Regulation 3. Good health Leukemia Myeloid Acute 030104 developmental biology fms-Like Tyrosine Kinase 3 Oncology CpG site Mutation Fms-Like Tyrosine Kinase 3 Cancer research DNMT3A CpG Islands Female Nucleophosmin hypomethylation |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/s41375-018-0084-2 |
| Popis: | Acute myeloid leukemia (AML) often harbors mutations in epigenetic regulators, and also has frequent DNA hypermethylation, including the presence of CpG island methylator phenotypes (CIMPs). Although global hypomethylation is well known in cancer, the question of whether distinct demethylator phenotypes (DMPs) exist remains unanswered. Using Illumina 450k arrays for 194 patients from The Cancer Genome Atlas, we identified two distinct DMPs by hierarchical clustering: DMP.1 and DMP.2. DMP.1 cases harbored mutations in NPM1 (94%), FLT3 (71%) and DNMT3A (61%). Surprisingly, only 40% of patients with DNMT3A mutations were DMP.1, which has implications for mechanisms of transformation by this mutation. In contrast, DMP.2 AML was comprised of patients with t(8;21), inv(16) or t(15;17), suggesting common methylation defects connect these disparate rearrangements. RNA-seq revealed upregulated genes functioning in immune response (DMP.1) and development (DMP.2). We confirmed these findings by integrating independent 450k data sets (236 additional cases), and found prognostic effects by DMP status, independent of age and cytogenetics. The existence of DMPs has implications for AML pathogenesis and may augment existing tools in risk stratification. |
| Databáze: | OpenAIRE |
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