Landmark analysis of DNMT3A mutations in hematological malignancies

Abstract

marrow was 118 days vs 140 days for Cdkn2a null irradiated (P ¼ .009). In all four groups, the majority of deaths were due to B-cell lymphoma/leukemia. We had hypothesized that irradiation would accelerate the development of disease in at least some of the recipient animals. Although there was substantial overlap of the survival curves of genetically matched irradiated and unirradiated groups, the survival curves of the irradiated groups appeared shifted to the left as compared with the respective unirradiated groups. Using the shortest time to leukemia in the control Cdkn2a null unirradiated group for comparison (97 days) we observed that 9 of 25 mice in the Cre/TA1 Cdkn2a irradiated group developed disease prior to this time, whereas only 2 of 24 mice in the Cre/TA1 Cdkn2a unirradiated group showed early disease (P ¼ .02; see Materials and Methods for statistical discussion). This finding suggests that some mice received cells for which low-dose radiation caused mutations that cooperated with TEL-AML1 expression and Cdkn2a loss to induce leukemia. Our results provide support for a model of TEL-AML1 leukemogenesis, in which environmental exposures may both enable expansion of initially disadvantaged TEL-AML1 expressing cells and cause cooperative leukemogenic mutations.

Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation

“…In T-cell acute lymphocytic leukemia/lymphoma (T-ALL), the R882 mutation is observed in 20% of patients with DNMT3A mutations, and about half of the remaining patients have biallelic mutations. 6,9 Together, these observations suggest that DNMT3A functions as a classic tumor suppressor, where most or all of the protein function must be lost for malignancy development.…”

“…[4][5][6] In AML, about 60% of patients exhibit heterozygous mutation at Arginine 882 (R882), which acts as a dominant negative, disrupting normal methylation function. 7,8 The remaining patients often have biallelic involvement, with compound heterozygous mutations or loss of homozygosity.…”

DNMT3A in Leukemia

“…3) (Cancer Genome Atlas Research 2013;Roller et al 2013). However, non-R882 missense and truncating mutations are found in each of the major domains (Cancer Genome Atlas Research 2013;Roller et al 2013).…”

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

“…The DNA methyltransferase 3A (DNMT3A) gene is mutated in approximately 37% of acute myeloid leukemia (AML) patients with a normal karyotype (and ~25% of all AML cases) (1) and is also frequently mutated in patients with myelodysplastic syndromes (MDS) (2) and T cell leukemias (3). These mutations are almost always heterozygous and have been demonstrated to be associated with high myeloblast counts, advanced age, and poor prognosis (1,(4)(5)(6)(7).…”