title: Dnmt3ahaploinsufficiency cooperates with oncogenicKrasto promote an early-onset T-cell acute lymphoblastic leukemia.
abstract: Mutations inDNA methyltransferase 3A (DNMT3A)are prevalent in various myeloid and lymphoid malignancies. The most commonDNMT3AR882 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 ofDNMT3Aregulates malignancies of different lineages in a dose-dependent manner. In a competitive transplant setting, the survival of recipients withKrasG12D/+;Dnmt3a+/-bone marrow (BM) cells was significantly shortened than that of recipients withKrasG12D/+cells. Moreover, all of the recipients withKrasG12D/+;Dnmt3a+/-cells developed a lethal T-cell acute lymphoblastic leukemia (T-ALL) without significant myeloproliferative neoplasm (MPN) phenotypes, while ~20% of recipients withKrasG12D/+cells developed MPN with or without T-ALL. This is in sharp contrast to the recipients withKrasG12D/+;Dnmt3a-/-cells, in which ~60% developed a lethal myeloid malignancy (MPN or acute myeloid leukemia [AML]). Our data suggest that in the context of oncogenicKras, loss ofDnmt3apromotes myeloid malignancies, whileDnmt3ahaploinsufficiency induces T-ALL. This dose-dependent phenotype is highly consistent with the prevalence ofDNMT3AR882 mutations in AML versus T-ALL in human.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-MadisonMadison, WI 53706, USA; Department and Institute of Physiology, National Yang-Ming UniversityTaipei 11221, Taiwan.
authors.forename: Yuan-I
authors.initials: YI
authors.lastname: Chang
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-MadisonMadison, WI 53706, USA; National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'an, P. R. China.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Kong
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center Madison, WI 53792, USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.affiliation: Department and Institute of Physiology, National Yang-Ming University Taipei 11221, Taiwan.
authors.forename: Po-Shu
authors.initials: PS
authors.lastname: Tu
authors.affiliation: Department and Institute of Physiology, National Yang-Ming University Taipei 11221, Taiwan.
authors.forename: Yi-Shan
authors.initials: YS
authors.lastname: Yu
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison Madison, WI 53706, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
keywords: DNA methylation; DNMT3A; KRAS; MPN; T-ALL