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Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):11306-11311. Epub 2016 Sep 21.

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

Author information

1
Institute for Cancer Genetics, Columbia University, New York, NY 10032.
2
Department of Systems Biology, Columbia University, New York, NY 10032; Department of Biomedical Informatics, Columbia University, New York, NY 10032; Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903.
3
Department of Systems Biology, Columbia University, New York, NY 10032; Department of Biomedical Informatics, Columbia University, New York, NY 10032.
4
Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; German Cancer Consortium, German Cancer Research Center, 69120 Heidelberg, Germany.
5
Hematology Service, Hospital Central de Asturias, 33011 Oviedo, Spain.
6
Molecular Oncology Laboratory, Instituto Universitario de Oncologia del Principado de Asturias, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain.
7
Department of Pediatrics, Columbia University Medical Center, New York, NY 10032.
8
Department of Hematology-Oncology, Saitama Children's Medical Center, Saitama 339-8551, Japan.
9
Onco-Hematology Division, Department, Salute della Donna e del Bambino (SDB), University of Padua, 35128 Padua, Italy.
10
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205; Department of Pathology, Ohio State University School of Medicine, Columbus, OH 43210; Department of Pediatrics, Ohio State University School of Medicine, Columbus, OH 43210; Children's Oncology Group, Arcadia, CA 91006.
11
Department of Biostatistics, University of Florida, Gainesville, FL 32611.
12
Department of Pediatrics, University of California, San Francisco, CA 94143; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115.
13
Institute for Cancer Genetics, Columbia University, New York, NY 10032; Department of Pathology, Columbia University Medical Center, New York, NY 10032 af2196@columbia.edu tp2151@columbia.edu rr2579@cumc.columbia.edu.
14
Department of Systems Biology, Columbia University, New York, NY 10032; Department of Biomedical Informatics, Columbia University, New York, NY 10032; af2196@columbia.edu tp2151@columbia.edu rr2579@cumc.columbia.edu.
15
Institute for Cancer Genetics, Columbia University, New York, NY 10032; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032; Department of Pathology, Columbia University Medical Center, New York, NY 10032 af2196@columbia.edu tp2151@columbia.edu rr2579@cumc.columbia.edu.

Abstract

Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wild-type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy.

KEYWORDS:

acute lymphoblastic leukemia; chemotherapy resistance; genome sequencing; relapsed leukemia

PMID:
27655895
PMCID:
PMC5056035
DOI:
10.1073/pnas.1608420113
[Indexed for MEDLINE]
Free PMC Article

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