Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.
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We thank the patients and clinical staff for the samples studied. L.Q. was supported by an Oxford-Celgene Fellowship; P.V. acknowledges funding from the MRC Disease Team Awards (G1000729/94931 and MR/L008963/1), MRC Molecular Haematology Unit and the Oxford Partnership Comprehensive Biomedical Research Centre (NIHR BRC Funding scheme. oxfbrc-2012-1). V.P.-L. and S.D.B. acknowledge funding from the French National Institute of Health (INSERM-AVIESAN), the National Cancer Institute (INCa-DGOS-Inserm_6043 and INCa 2012-1-RT-09), SIRIC-SOCRATE 2.0 and the Fondation Association pour la Recherche sur le Cancer (ARC, Programme). M.D.D. is funded by a fellowship from the Institut National du Cancer (INCa-DGOS_5733). M.H. is supported as a fellow of the Fondation Philanthropia, Ecole des Sciences du Cancer, Gustave Roussy, Villejuif, France. We acknowledge the Core Flow Cytometry and Next Generation Sequencing Facilities at the WIMM; the Imaging, Cytometry and Integrated Biology platforms at Gustave Roussy (P. Rameau, Y. Lecluse, N. Droin, M. K. Diop and UMS AMMICa); the clinical departments at Gustave Roussy (J.-B. Micol for clinical specimens; N. Auger for cytogenetic analyses; and C. Marzac and E. Leclercq for FLT3 genotyping) and Memorial Sloan Kettering. R.L.L. is supported by grants from the NIH, including R35 CA197594-01A1 and a Memorial Sloan Kettering Cancer Center Support Grant (NIH P30 CA008748, including a supplement to R.L.L.). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
P.V. has received research grant support from Celgene and is on its speaker bureau. L.Q. has received research grant support from Celgene.
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Quek, L., David, M.D., Kennedy, A. et al. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat Med 24, 1167–1177 (2018). https://doi.org/10.1038/s41591-018-0115-6
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