Oncotarget

Priority Research Papers:

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

Jennifer L. Poitras, Diane Heiser, Li Li, Bao Nguyen, Kozo Nagai, Amy S. Duffield, Christopher Gamper and Donald Small _

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Oncotarget. 2016; 7:69124-69135. https://doi.org/10.18632/oncotarget.11986

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Abstract

Jennifer L. Poitras1, Diane Heiser1, Li Li1, Bao Nguyen1, Kozo Nagai1, Amy S. Duffield2, Christopher Gamper1,3 and Donald Small1,3

1 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

3 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Correspondence to:

Donald Small, email:

Keywords: FLT3, internal tandem duplication, DNMT3a, acute myeloid leukemia, mouse model

Received: May 20, 2016 Accepted: September 02, 2016 Published: September 12, 2016

Abstract

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 Flt3ITD/+ mice in a dose dependent manner. As expected, pIpC treated Flt3ITD/+ mice solely developed MPN, while Flt3ITD/+;Dnmt3af/f and Flt3ITD/+;Dnmt3af/+ 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 Flt3ITD/+;Dnmt3af/f model may serve as a valuable resource for delineating effective therapeutic strategies in two clinically relevant contexts.


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