Data from DNMT3A Haploinsufficiency Transforms <i>FLT3</i><sup>ITD</sup> Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia

Abstract

<div>Abstract<p>Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the <i>de novo</i> DNA methyltransferase <i>DNMT3A</i> and the FMS related tyrosine kinase 3 <i>(FLT3)</i> are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with <i>Flt3</i>-internal tandem duplication (<i>Flt3</i><sup>ITD</sup>) and inducible deletion of <i>Dnmt3a</i> spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single <i>Dnmt3a</i> floxed allele, revealing the oncogenic potential of <i>Dnmt3a</i> haploinsufficiency. <i>FLT3</i><sup>ITD</sup><i>/DNMT3A</i>-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing <i>Dnmt3a</i> expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that <i>Dnmt3a</i>-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, <i>Dnmt3a</i> haploinsufficiency transforms <i>Flt3</i><sup>ITD</sup> myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation.</p><p><b>Significance:</b><i>DNMT3A</i> haploinsufficiency results in reversible epigenetic alterations that transform FLT3<sup>ITD</sup>-mutant myeloproliferative neoplasm into AML. <i>Cancer Discov; 6(5); 501–15. ©2016 AACR.</i></p><p>This article is highlighted in the In This Issue feature, p. 461</p></div>