![]() Analysis of paired diagnosis/relapse samples did not identify second site mutations in IDH2 at relapse. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones less frequently, treatment promoted differentiation of non-mutant cells. Pre-therapy IDH2 mutant clones showed variable differentiation arrest. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated relapsed/ refractory AML patients by promoting leukemic cell differentiation. In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Mutations in the gene encoding isocitrate dehydrogenase 2 ( IDH2) occur in several types of cancer, including acute myeloid leukemia (AML).
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