Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies

Remethylation of Dnmt3a −/− hematopoietic cells is associated with partial correction of gene dysregulation and reduced myeloid skewing

“…Murine hematopoietic cells that are constitutively deficient for Dnmt3a have thousands of DMRs that possess a focal, canonical hypomethylation phenotype (13,16). Dnmt3a deficiency is associated with expansion and immortalization of hematopoietic stem cells, a block in hematopoietic differentiation, and the development of myeloid and lymphoid malignancies after a long latent period (17,23,24).…”

“…Young mice with Dnmt3a deficiency have essentially normal blood counts and hematopoietic development, despite the hypomethylation phenotype. While humans with complete DNMT3A deficiency in their bone marrow cells have not been described, many patients with ARCH-and some with AML-have heterozygous loss-of-function mutations in DNMT3A that cause haploinsufficiency (16). In mice, Dnmt3a haploinsufficiency is associated with a very subtle DNA hypomethylation phenotype in hematopoietic cells, myeloid lineage expansion over time, and the development of myeloid malignancies after a very long latent period (∼18 mo), during which cooperating mutations are acquired (16).…”

“…While humans with complete DNMT3A deficiency in their bone marrow cells have not been described, many patients with ARCH-and some with AML-have heterozygous loss-of-function mutations in DNMT3A that cause haploinsufficiency (16). In mice, Dnmt3a haploinsufficiency is associated with a very subtle DNA hypomethylation phenotype in hematopoietic cells, myeloid lineage expansion over time, and the development of myeloid malignancies after a very long latent period (∼18 mo), during which cooperating mutations are acquired (16). All of these observations suggest that Dnmt3a haploinsufficiency and deficiency create an epigenetic state that somehow facilitates the acquisition of cooperating mutations and transformation.…”

“…In AML cells that are WT for DNMT3A, a large number of CpG islands (CGI) are hypermethylated (14), a finding that is common to many cancer types; however, this phenotype is mitigated in R882 mutant AMLs, suggesting that CGI hypermethylation is, in fact, caused by DNMT3A activity. The genomes of DNMT3A R882 mutant AML samples also have many hypomethylated DMRs that are not associated with CGI, suggesting that there are additional regions in hematopoietic cell genomes where DNA methylation is DNMT3Adependent (13)(14)(15)(16)(17)(18)). Likewise, a child with Tatton-Brown-Rahman syndrome caused by an inherited DNMT3A R882H mutation was found to have a focal hypomethylation phenotype in his nonleukemic hematopoietic cells (14), suggesting that this epigenetic state exists before transformation, and may therefore be relevant for the initiation of myeloid malignancies (14,(19)(20)(21)(22).…”

Advances in understanding the pathogenesis of acquired aplastic anaemia

“…DNMT3A encodes one subunit of an enzyme responsible for de novo methylation of DNA. Here one finds mostly missense mutations, with a recurrent mutation at codon 882: this has been shown to act as dominant‐negative by interfering with the dimerization of the DNMT3A protein (Russler‐Germain et al , ), but other mutations may exert their effect through haploinsufficiency (Cole et al , ). Each one of these genes must have an important role in development: indeed, germ‐line mutations cause multiple complex developmental abnormalities (Table ).…”