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Nat Commun. 2014 Mar 24;5:3469. doi: 10.1038/ncomms4469.

Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia.

Author information

1
1] Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
2
Department of Internal Medicine III, University of Ulm, Ulm 89081, Germany.
3
Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
4
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
5
Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
6
Biostatistics & Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
7
Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
8
Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
9
Oncoematologia Pediatrica, Azienda Policlinico OVE, 95125, Catania, Italy.

Abstract

Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signalling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.

PMID:
24662245
PMCID:
PMC4016990
DOI:
10.1038/ncomms4469
[Indexed for MEDLINE]
Free PMC Article

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