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

Abstract

SUMMARY 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 over-expressed 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.

Mature lymphoid malignancies: origin, stem cells, and chronicity

“…That CD34 1 stem cells are the apex of CLL pathogenesis is further supported by a mouse model with long-term conditional inactivation of DNMT3A in HSCs, which develop a CLL phenotype. 100 As mentioned, HCL patients have been found to harbor the BRAFV600E mutation in both mature lymphocytes, B-cell precursors, and human CD34 1 stem cells. 53 The same study transplanted highly purified stem cells from an untreated HCL patient into mice.…”

New insights on the role of DNA methylation from a global view

“…Indeed, studies in mouse models support that mutations in DNMT1 and DNMT3A promote tumor growth of T cell lymphoma and lung cancer, respectively (78,79). A recent study identified DNMT3A as a haploinsufficient tumor suppressor in chronic lymphocytic leukemia (CLL), revealing that decreased levels of DNMT3A are sufficient for disease induction, even though with a later onset than in case of its lack in DNMT3A-deficient mice (80). Both DNMT3A +/and DNMT3A Δ/Δ CLL cells share a common set of DNA hypomethylated and overexpressed genes that were assigned to a role in cancer.…”

B-cell tumor development in Tet2-deficient mice

“…8 However, no major member of the DNA methylation control pathway was recurrently found mutated in CLL and malignant B-cell differentiation. [12][13][14][15][16] Another player in B-cell malignant development is the activationinduced cytidine deaminase (AID) gene, which encodes a cytidine deaminase and is known to initiate both class switch recombination and somatic hypermutation, 2 main mechanisms implicated in the maturation of the antibody response. AID expression is tightly regulated, and its aberrant activity has been shown to induce mutations in nonimmunoglobulin genes, thus contributing to cellular transformation.…”