Dnmt3a haploinsufficiency cooperates with oncogenic Kras to promote an early-onset T-cell acute lymphoblastic leukemia.

ABSTRACT: Mutations in DNA methyltransferase 3A (DNMT3A) are prevalent in various myeloid and lymphoid malignancies. The most common DNMT3A R882 mutations inhibit methyltransferase activity of the remaining wild-type DNMT3A proteins at a heterozygous state due to their dominant-negative activity. Reports and COSMIC database analysis reveal significantly different frequencies of R882 mutations in myeloid versus T-cell malignancies, inspiring us to investigate whether downregulation of DNMT3A regulates malignancies of different lineages in a dose-dependent manner. In a competitive transplant setting, the survival of recipients with Kras^G12D/+ ; Dnmt3a^+/- bone marrow (BM) cells was significantly shortened than that of recipients with Kras^G12D/+ cells. Moreover, all of the recipients with Kras^G12D/+ ; Dnmt3a^+/- cells developed a lethal T-cell acute lymphoblastic leukemia (T-ALL) without significant myeloproliferative neoplasm (MPN) phenotypes, while ~20% of recipients with Kras^G12D/+ cells developed MPN with or without T-ALL. This is in sharp contrast to the recipients with Kras^G12D/+ ; Dnmt3a^-/- cells, in which ~60% developed a lethal myeloid malignancy (MPN or acute myeloid leukemia [AML]). Our data suggest that in the context of oncogenic Kras, loss of Dnmt3a promotes myeloid malignancies, while Dnmt3a haploinsufficiency induces T-ALL. This dose-dependent phenotype is highly consistent with the prevalence of DNMT3A R882 mutations in AML versus T-ALL in human.

SUBMITTER: Chang YI 

PROVIDER: S-EPMC5376023 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature