Decreases in different Dnmt3b activities drive distinct development of hematologic malignancies in mice

Abstract

DNA methylation regulates gene transcription and is involved in various physiological processes in mammals, including development and hematopoiesis. It is catalyzed by DNA methyltransferases including Dnmt1, Dnmt3a, and Dnmt3b. For Dnmt3b, its effects on transcription can result from its own DNA methylase activity, the recruitment of other Dnmts to mediate methylation, or transcription repression in a methylation-independent manner. Low-frequency mutations in human DNMT3B are found in hematologic malignancies including cutaneous T-cell lymphomas, hairy cell leukemia, and diffuse large B-cell lymphomas. Moreover, Dnmt3b is a tumor suppressor in oncogene-driven lymphoid and myeloid malignancies in mice. However, it is poorly understood how the different Dnmt3b activities contribute to these outcomes. We modulated Dnmt3b activity in vivo by generating Dnmt3b +/− mice expressing one wild-type allele as well as Dnmt3b +/CI and Dnmt3b CI/CI mice where one or both alleles express catalytically inactive Dnmt3b CI . We show that 43% of Dnmt3b +/− mice developed T-cell lymphomas, chronic lymphocytic leukemia, and myeloproliferation over 18 months, thus resembling phenotypes previously observed in Dnmt3a +/− mice, possibly through regulation of shared target genes. Interestingly, Dnmt3b +/CI and Dnmt3b CI/CI mice survived postnatal development and were affected by B-cell rather than T-cell malignancies with decreased penetrance. Genome-wide hypomethylation, increased expression of oncogenes such as Jdp2, STAT1, and Trip13, and p53 downregulation were major events contributing to Dnmt3b +/− lymphoma development. We conclude that Dnmt3b catalytic activity is critical to prevent B-cell transformation in vivo , whereas accessory and methylation-independent repressive functions are important to prevent T-cell transformation.

Misregulation of the expression and activity of DNA methyltransferases in cancer

“…In Myc-induced lymphoma, expedited lymphomagenesis is associated with increased expression of a truncated catalytically-inactive dominant-negative isoform, DNMT3B7 ( 196 ). This observation is corroborated by a recent study that showed that mice expressing a catalytically-inactive DNMT3B isoform from one or both alleles develop B-cell lymphomas among other hematologic malignancies ( 197 ). In non-small cell lung cancer (NSCLC), the ΔDNMT3B subfamily was described, consisting of at least seven DNMT3B variants resulting from alternative splicing, some lacking enzymatic activity ( 198 ).…”

Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

“…Moreover, both in AML and DLBCL, high DNMT3B levels are correlated with a bad prognosis and a more aggressive disease (141,142). However, while most studies indicate that DNMT3B has oncogenic properties in hematological cancers, some studies have also reported the opposite (143)(144)(145). For example, Dnmt3b deletion in the MLL-AF9 driven AML mouse model led to accelerated progression (146).…”

“…For example, Dnmt3b deletion in the MLL-AF9 driven AML mouse model led to accelerated progression (146). Furthermore, Dnmt3b haploinsufficiency in mice resulted in the development of various hematologic malignancies, including TCL (145). In MM, Amodio et al reported an inverse correlation between miR-29b and DNMT3B levels and showed that targeting DNMT3A/B using miR-29b mimics reduces MM cell growth, indicating that DNMT3A/B has an oncogenic role in MM (138).…”

“…For example, Dnmt3b deletion in the MLL-AF9 driven AML mouse model led to accelerated progression ( 146 ). Furthermore, Dnmt3b haploinsufficiency in mice resulted in the development of various hematologic malignancies, including TCL ( 145 ). In MM, Amodio et al.…”

Genomic Uracil and Aberrant Profile of Demethylation Intermediates in Epigenetics and Hematologic Malignancies

“…In humans, mutations in DNMT3B have been found in several hematological malignancies including cutaneous T-cell lymphomas and B-cell lymphomas [80]. Moreover, Dnmt3b-deficient mice display genome-wide hypomethylation, increased expression of several oncogenes, and develop T-cell lymphomas and chronic lymphocytic leukemia [81]. TET1 was identified as a fusion partner of the mixed-lineage leukemia (MLL) gene from the breakpoint of chromosomal translocation in acute myeloid leukemia (AML) [82], and loss of TET2 is strongly associated with myelodysplastic syndromes, myeloproliferative neoplasms, and myeloid leukemias [83].…”