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

2016; National Academy of Sciences; Volume: 113; Issue: 40 Linguagem: Inglês

10.1073/pnas.1608420113

1091-6490

Koichi Oshima, Hossein Khiabanian, Ana C. da Silva-Almeida, Gannie Tzoneva, Francesco Abate, Alberto Ambesi‐Impiombato, Marta Sánchez-Martín, Zachary Carpenter, Alex Penson, Arianne Pérez-García, Cornelia Eckert, Concepción Nicolás, Milagros Balbı́n, Maria Luisa Sulis, Motohiro Kato, Katsuyoshi Koh, Maddalena Paganin, Giuseppe Basso, Julie M. Gastier‐Foster, Meenakshi Devidas, Mignon L. Loh, Renate Kirschner‐Schwabe, Teresa Palomero, Raúl Rabadán, Adolfo A. Ferrando,

Cancer therapeutics and mechanisms

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 in disease progression and defining the process of clonal evolution leading to relapse. These analyses revealed that ALL relapse emerges from subclonal populations sharing only part of the mutations present in the dominant leukemia population found at diagnosis. Moreover, we show mutations in genes implicated in chemotherapy resistance pathways at relapse. RAS mutations are highly prevalent in high-risk ALL, yet their capacity to confer resistance to methotrexate and sensitivity to vincristine, two core drugs used in the treatment of ALL, influences their positive or negative selection at relapse.