Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

Staci L. Haney, G. Michael Upchurch, Jana Opavska, David L Klinkebiel, Ryan A. Hlady, Abhinav Suresh, Samuel Jay Pirruccello, Vipul Shukla, Runqing Lu, Stefan Costinean, A Angie Rizzino, Adam R Karpf, Shantaram S Joshi, Patrick Swanson, Rene Opavsky

Research output: Contribution to journalArticle

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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 Dnmt3aδ/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 Dnmt3aδ/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.

Original languageEnglish (US)
Pages (from-to)1190-1201
Number of pages12
JournalCell Reports
Volume15
Issue number6
DOIs
StatePublished - May 10 2016

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B-Cell Chronic Lymphocytic Leukemia
Genes
Loss of Heterozygosity
Methylation
Cytosine
Gene expression
Tumors
Hematologic Neoplasms
DNA
Lymphoma
Leukemia
Genome
Gene Expression
Neoplasms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a. / Haney, Staci L.; Upchurch, G. Michael; Opavska, Jana; Klinkebiel, David L; Hlady, Ryan A.; Suresh, Abhinav; Pirruccello, Samuel Jay; Shukla, Vipul; Lu, Runqing; Costinean, Stefan; Rizzino, A Angie; Karpf, Adam R; Joshi, Shantaram S; Swanson, Patrick; Opavsky, Rene.

In: Cell Reports, Vol. 15, No. 6, 10.05.2016, p. 1190-1201.

Research output: Contribution to journalArticle

Haney, Staci L. ; Upchurch, G. Michael ; Opavska, Jana ; Klinkebiel, David L ; Hlady, Ryan A. ; Suresh, Abhinav ; Pirruccello, Samuel Jay ; Shukla, Vipul ; Lu, Runqing ; Costinean, Stefan ; Rizzino, A Angie ; Karpf, Adam R ; Joshi, Shantaram S ; Swanson, Patrick ; Opavsky, Rene. / Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a. In: Cell Reports. 2016 ; Vol. 15, No. 6. pp. 1190-1201.
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