| Literature DB >> 27134162 |
Staci L Haney1, G Michael Upchurch2, Jana Opavska2, David Klinkebiel3, Ryan A Hlady4, Abhinav Suresh2, Samuel J Pirruccello5, Vipul Shukla1, Runqing Lu1, Stefan Costinean6, Angie Rizzino7, Adam R Karpf2, Shantaram Joshi8, Patrick Swanson9, Rene Opavsky10.
Abstract
DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA, and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here, we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that, by 16 months of age, 65% of Dnmt3a(+/-) mice develop a CLL-like disease, and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a(+/-) and Dnmt3a(Δ/Δ) CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene expression analysis identified 26 hypomethylated and overexpressed genes common to both Dnmt3a(+/-) and Dnmt3a(Δ/Δ) CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.Entities:
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Year: 2016 PMID： 27134162 PMCID： PMC4864108 DOI： 10.1016/j.celrep.2016.04.004
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423