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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • DNA Primers / genetics
  • Epigenesis, Genetic / genetics*
  • Exons / genetics
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Molecular Sequence Data
  • Mutation / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Recurrence
  • Sequence Analysis, DNA
  • Treatment Failure*


  • DNA Primers
  • Histone-Lysine N-Methyltransferase
  • SETD2 protein, human