Data from IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia

Abstract

<div>Abstract<p>IDH1 and IDH2 mutations occur frequently in acute myeloid leukemia (AML) and other cancers. The mutant isocitrate dehydrogenase (IDH) enzymes convert α-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-KG–dependent dioxygenases. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with <i>nucleophosmin1</i> (NPM)<sup>+/−</sup> hematopoietic stem/progenitor cells cotransduced with four mutant genes (<i>NPMc</i>, <i>IDH2/R140Q</i>, <i>DNMT3A/R882H</i>, and <i>FLT3/ITD</i>), which often occur simultaneously in human AML patients. Conditional deletion of <i>IDH2/R140Q</i> blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q was necessary for the engraftment or survival of NPMc<sup>+</sup> cells <i>in vivo</i>. Gene expression analysis indicated that NPMc increased expression of Hoxa9. IDH2/R140Q also increased the level of Meis1 and activated the hypoxia pathway in AML cells. IDH2/R140Q decreased the 5hmC modification and expression of some differentiation-inducing genes (<i>Ebf1</i> and <i>Spib</i>). Taken together, our results indicated that IDH2 mutation is critical for the development and maintenance of AML stem-like cells, and they provided a preclinical justification for targeting mutant IDH enzymes as a strategy for anticancer therapy. <i>Cancer Res; 75(10); 2005–16. ©2015 AACR</i>.</p></div>