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

Brenton G. Mar, Lars B. Bullinger, Kathleen M. McLean, Peter V. Grauman, Marian H. Harris, Kristen Stevenson, Donna S. Neuberg, Amit U. Sinha, Stephen E. Sallan, Lewis B. Silverman, Andrew L. Kung, Luca Lo Nigro, Benjamin L. Ebert and Scott A. Armstrong ()
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Brenton G. Mar: Dana Farber Cancer Institute
Lars B. Bullinger: University of Ulm
Kathleen M. McLean: Dana Farber Cancer Institute
Peter V. Grauman: Brigham and Women's Hospital, Harvard Medical School
Marian H. Harris: Boston Children’s Hospital
Kristen Stevenson: Biostatistics & Computational Biology, Dana Farber Cancer Institute
Donna S. Neuberg: Biostatistics & Computational Biology, Dana Farber Cancer Institute
Amit U. Sinha: Memorial Sloan-Kettering Cancer Center
Stephen E. Sallan: Dana Farber Cancer Institute
Lewis B. Silverman: Dana Farber Cancer Institute
Andrew L. Kung: Columbia University Medical Center
Luca Lo Nigro: Oncoematologia Pediatrica, Azienda Policlinico OVE
Benjamin L. Ebert: Brigham and Women's Hospital, Harvard Medical School
Scott A. Armstrong: Memorial Sloan-Kettering Cancer Center

Nature Communications, 2014, vol. 5, issue 1, 1-6

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4469

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