Mutant <i>Idh2</i> Cooperates with a <i>NUP98-HOXD13</i> Fusion to Induce Early Immature Thymocyte Precursor ALL.

Abstract

Mutations in the isocitrate dehydrogenase 1 (<i>IDH1</i>) and <i>IDH2</i> genes are frequently observed in a wide variety of hematologic malignancies, including myeloid and T-cell leukemias. In this study, we generated <i>Idh2^R140Q</i> transgenic mice to examine the role of the <i>Idh2^R140Q</i> mutation in leukemia. No leukemia developed in <i>Idh2^R140Q</i> transgenic mice, suggesting a need for additional genetic events for leukemia development. Because myeloid cells from <i>NUP98-HOXD13</i> fusion (<i>NHD13</i>) transgenic mice frequently acquire somatic <i>Idh</i> mutations when they transform to acute myeloid leukemia, we generated <i>Idh2^R140Q/NHD13</i> double transgenic mice. <i>Idh2^R140Q/NHD13</i> transgenic mice developed an immature T-cell leukemia with an immunophenotype similar to double-negative 1 (DN1) or DN2 thymocytes. <i>Idh2^R140Q/NHD13</i> leukemic cells were enriched for an early thymic precursor transcriptional signature, and the gene expression profile for <i>Idh2^R140Q/NHD13</i> DN1/DN2 T-ALL closely matched that of human early/immature T-cell precursor (EITP) acute lymphoblastic leukemia (ALL). Moreover, recurrent mutations found in patients with EITP ALL, including <i>KRAS, PTPN11, JAK3, SH2B3</i>, and <i>EZH2</i> were also found in <i>Idh2^R140Q/NHD13</i> DN1/DN2 T-ALL. <i>In vitro</i> treatment of <i>Idh2^R140Q/NHD13</i> thymocytes with enasidenib, a selective inhibitor of mutant IDH2, led to a marked decrease in leukemic cell proliferation. These findings demonstrate that <i>Idh2^R140Q/NHD13</i> mice can serve as a useful <i>in vivo</i> model for the study of early/immature thymocyte precursor acute lymphoblastic leukemia development and therapy. SIGNIFICANCE: T-cell leukemia induced in <i>Idh2^R140Q/NUP98-HOXD13</i> mice is immunophenotypically, transcriptionally, and genetically similar to human EITP ALL, providing a model for studying disease development and treatment.