Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib

Autor: George S. Vassiliou, Eytan M. Stein, Cyril Quivoron, Ross L. Levine, Lynn Quek, Stéphane de Botton, Paresh Vyas, Bilyana Stoilova, Michael Amatangelo, Alison Kennedy, M. S. Vijayabaskar, Alan Shih, O. Bernard, Virginie Penard-Lacronique, Katharine E. Yen, Véronique Saada, Maël Heiblig, Samar Alsafadi, Marlen Metzner, Kyle J. MacBeth, Muriel D. David, Andy Peniket, Anjan Thakurta, Sam Agresta, Christophe Willekens
Rok vydání: 2018
Předmět:
Neoplastic Stem Cells/drug effects
0301 basic medicine
Myeloid
Mutation/genetics
Cellular differentiation
Leukemia
Myeloid
Acute/drug therapy
Aminopyridines
Enasidenib
Biology
Somatic evolution in cancer
General Biochemistry
Genetics and Molecular Biology
Immunophenotyping
Cohort Studies
03 medical and health sciences
0302 clinical medicine
medicine
Humans
Neoplasm Recurrence
Local/pathology
Triazines
Myeloid leukemia
Cell Differentiation
General Medicine
medicine.disease
Isocitrate Dehydrogenase
Clone Cells
Hematopoiesis
Aminopyridines/pharmacology
Leukemia
Myeloid
Acute
Leukemia
Haematopoiesis
Triazines/pharmacology
030104 developmental biology
medicine.anatomical_structure
Cell Differentiation/drug effects
030220 oncology & carcinogenesis
Isocitrate Dehydrogenase/antagonists & inhibitors
Mutation
Neoplastic Stem Cells
Cancer research
Neoplasm Recurrence
Local
Zdroj: Quek, L, David, M D, Kennedy, A, Metzner, M, Amatangelo, M, Shih, A, Stoilova, B, Quivoron, C, Heiblig, M, Willekens, C, Saada, V, Alsafadi, S, Vijayabaskar, M S, Peniket, A, Bernard, O A, Agresta, S, Yen, K, MacBeth, K, Stein, E, Vassiliou, G S, Levine, R, De Botton, S, Thakurta, A, Penard-Lacronique, V & Vyas, P 2018, ' Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib ', Nature Medicine, vol. 24, no. 8, pp. 1167-1177 . https://doi.org/10.1038/s41591-018-0115-6
ISSN: 1546-170X
1078-8956
DOI: 10.1038/s41591-018-0115-6
Popis: 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.
Databáze: OpenAIRE
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