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, Donald Small

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)69124-69135
Number of pages12
JournalOncotarget
Volume7
Issue number43
DOIs
StatePublished - 2016

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Mutation
Neoplasms
Hematologic Neoplasms
Leukemia
Phosphotransferases
Alleles
Recurrence
Incidence
Therapeutics

Keywords

  • Acute myeloid leukemia
  • DNMT3a
  • FLT3
  • Internal tandem duplication
  • Mouse model

ASJC Scopus subject areas

  • Oncology

Cite this

Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model. / Poitras, Jennifer L.; Heiser, Diane; Li, Li; Nguyen, Bao; Nagai, Kozo; Duffield, Amy S; Gamper, Christopher; Small, Donald.

In: Oncotarget, Vol. 7, No. 43, 2016, p. 69124-69135.

Research output: Contribution to journalArticle

Poitras, Jennifer L. ; Heiser, Diane ; Li, Li ; Nguyen, Bao ; Nagai, Kozo ; Duffield, Amy S ; Gamper, Christopher ; Small, Donald. / Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model. In: Oncotarget. 2016 ; Vol. 7, No. 43. pp. 69124-69135.
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AB - 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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