The genetic basis of early T-cell precursor acute lymphoblastic leukaemia

Nature. 2012 Jan 11;481(7380):157-63. doi: 10.1038/nature10725.

Abstract

Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

Publication types

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

MeSH terms

  • Age of Onset
  • Child
  • DNA Copy Number Variations / genetics
  • Genes, ras / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genome, Human / genetics
  • Genomics
  • Hematopoiesis / genetics
  • Histones / metabolism
  • Humans
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Molecular Sequence Data
  • Mutation / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Receptors, Interleukin-7 / genetics
  • Sequence Analysis, DNA
  • Signal Transduction / genetics
  • Stem Cells / metabolism
  • Stem Cells / pathology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Translocation, Genetic / genetics

Substances

  • Histones
  • Receptors, Interleukin-7
  • Janus Kinases

Associated data

  • GENBANK/JF736506
  • GEO/GSE28703
  • GEO/GSE33315