Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

• DOI: 10.1073/pnas.1608420113
• Publication Date: 2016-09-22T03:18:53Z
• Authors: Koichi Oshima; Hossein Khiabanian; Ana C. da Silva-A...; Gannie Tzoneva; Francesco Abate; Alberto Ambesi-Im...; Marta Sanchez-Martin; Zachary Carpenter; Alex Penson; Arianne Perez-Garcia; Cornelia Eckert; Concepción Nicolas; Milagros Balbin; Maria Luisa Sulis; Motohiro Kato; Katsuyoshi Koh; Maddalena Paganin; Giuseppe Basso; Julie M. Gastier-...; Meenakshi Devidas; Mignon L. Loh; Renate Kirschner-...; Teresa Palomero; Raul Rabadan; Adolfo A. Ferrando
• Keywords: 0301 basic medicine; Base Sequence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; 3. Good health; Clonal Evolution; 03 medical and health sciences; Genes, ras; Methotrexate; Drug Resistance, Neoplasm; Vincristine; Cell Line, Tumor; Mutation; Humans

Significance Relapsed acute lymphoblastic leukemia (ALL) is associated with chemotherapy resistance and poor prognosis. This study analyzes the emergence of acquired mutations in relapsed ALL samples, identifying genes implicated disease progression defining process clonal evolution leading to relapse. These analyses revealed that relapse emerges from subclonal populations sharing only part present dominant population found at diagnosis. Moreover, we show pathways RAS are highly prevalent high-risk ALL, yet their capacity confer methotrexate sensitivity vincristine, two core drugs used treatment influences positive or negative selection