Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model

作者：Poitras Jennifer L; Heiser Diane; Li Li; Bao Nguyen; Nagai Kozo; Duffield Amy S; Gamper Christopher; Small Donald^*

来源：Oncotarget, 2016, 7(43): 69124-69135.

DOI：10.18632/oncotarget.11986

• FLT3
• internal tandem duplication
• DNMT3a
• acute myeloid leukemia
• mouse model

Internal tandem duplications of the juxtamembrane domain of FLT3 (FLT3/ITD) are among the most common mutations in Acute Myeloid Leukemia (AML). Resulting in constitutive activation of the kinase, FLT3/ITD portends a particularly poor prognosis, with reduced overall survival and increased rates of relapse. We previously generated a knock-in mouse, harboring an internal tandem duplication at the endogenous Flt3 locus, which develops a fatal myeloproliferative neoplasm (MPN), but fails to develop acute leukemia, suggesting additional mutations are necessary for transformation. To investigate the potential cooperativity of FLT3/ITD and mutant DNMT3A, we bred a conditional Dnmt3a knockout to a substrain of our Flt3/ITD knock-in mice, and found deletion of Dnmt3a significantly reduced median survival of Flt3(ITD/+) mice in a dose dependent manner. As expected, pIpC treated Flt3(ITD/+) mice solely developed MPN, while Flt3(ITD/+); Dnmt3a(f/f) and Flt3(ITD/+); Dnmt3a(f/+) developed a spectrum of neoplasms, including MPN, T-ALL, and AML. Functionally, FLT3/ITD and DNMT3A deletion cooperate to expand LT-HSCs, which exhibit enhanced self-renewal in serial re-plating assays. These results illustrate that DNMT3A loss cooperates with FLT3/ITD to generate hematopoietic neoplasms, including AML. In combination with FLT3/ITD, homozygous Dnmt3a knock-out results in reduced time to disease onset, LT-HSC expansion, and a higher incidence of T-ALL compared with loss of just one allele. The co-occurrence of FLT3 and DNMT3A mutations in AML, as well as subsets of T-ALL, suggests the Flt3(ITD/+); Dnmt3a(f/f) model may serve as a valuable resource for delineating effective therapeutic strategies in two clinically relevant contexts.

• 出版日期2016-10-25