Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

Haematologica. 2015 Oct;100(10):1301-10. doi: 10.3324/haematol.2015.130179. Epub 2015 Jul 23.

Abstract

T-cell acute lymphoblastic leukemia is caused by the accumulation of multiple oncogenic lesions, including chromosomal rearrangements and mutations. To determine the frequency and co-occurrence of mutations in T-cell acute lymphoblastic leukemia, we performed targeted re-sequencing of 115 genes across 155 diagnostic samples (44 adult and 111 childhood cases). NOTCH1 and CDKN2A/B were mutated/deleted in more than half of the cases, while an additional 37 genes were mutated/deleted in 4% to 20% of cases. We found that IL7R-JAK pathway genes were mutated in 27.7% of cases, with JAK3 mutations being the most frequent event in this group. Copy number variations were also detected, including deletions of CREBBP or CTCF and duplication of MYB. FLT3 mutations were rare, but a novel extracellular mutation in FLT3 was detected and confirmed to be transforming. Furthermore, we identified complex patterns of pairwise associations, including a significant association between mutations in IL7R-JAK genes and epigenetic regulators (WT1, PRC2, PHF6). Our analyses showed that IL7R-JAK genetic lesions did not confer adverse prognosis in T-cell acute lymphoblastic leukemia cases enrolled in the UK ALL2003 trial. Overall, these results identify interconnections between the T-cell acute lymphoblastic leukemia genome and disease biology, and suggest a potential clinical application for JAK inhibitors in a significant proportion of patients with T-cell acute lymphoblastic leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Clonal Evolution / genetics
  • DNA Copy Number Variations
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Genetic Association Studies
  • Genetic Variation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Janus Kinases / genetics*
  • Janus Kinases / metabolism
  • Male
  • Mutation*
  • Polymorphism, Single Nucleotide
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / diagnosis
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Prognosis
  • Receptors, Interleukin-7 / genetics*
  • Receptors, Interleukin-7 / metabolism
  • Reproducibility of Results
  • Signal Transduction

Substances

  • Receptors, Interleukin-7
  • Janus Kinases