Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations

Oncotarget. 2016 Oct 4;7(40):65485-65503. doi: 10.18632/oncotarget.11796.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with variable prognosis. It represents 15% of diagnosed pediatric ALL cases and has a threefold higher incidence among males. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined. Using an integrative approach combining genomic and transcriptomic data, we molecularly characterized 30 pediatric T-ALLs and identified common recurrent T-ALL targets such as FBXW7, JAK1, JAK3, PHF6, KDM6A and NOTCH1 as well as novel candidate T-ALL driver mutations including the p.R35L missense mutation in splicesome factor U2AF1 found in 3 patients and loss of function mutations in the X-linked tumor suppressor genes MED12 (frameshit mutation p.V167fs, splice site mutation g.chrX:70339329T>C, missense mutation p.R1989H) and USP9X (nonsense mutation p.Q117*). In vitro functional studies further supported the putative role of these novel T-ALL genes in driving transformation. U2AF1 p.R35L was shown to induce aberrant splicing of downstream target genes, and shRNA knockdown of MED12 and USP9X was shown to confer resistance to apoptosis following T-ALL relevant chemotherapy drug treatment in Jurkat leukemia cells. Interestingly, nearly 60% of novel candidate driver events were identified among immature T-ALL cases, highlighting the underlying genomic complexity of pediatric T-ALL, and the need for larger integrative studies to decipher the mechanisms that contribute to its various subtypes and provide opportunities to refine patient stratification and treatment.

Keywords: MED12; T-cell acute lymphoblastic leukemia; U2AF1; USP9X; X-linked tumor suppressor.

MeSH terms

  • Alternative Splicing
  • Apoptosis / genetics
  • Carcinogenesis / genetics
  • Carrier Proteins / genetics
  • Child
  • Codon, Nonsense / genetics*
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm / genetics
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • Female
  • Genetic Association Studies
  • Genome
  • Histone Demethylases / genetics
  • Humans
  • Janus Kinase 1 / genetics
  • Janus Kinase 3 / genetics
  • Jurkat Cells
  • Male
  • Mediator Complex / genetics*
  • Mutation, Missense / genetics*
  • Nuclear Proteins / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • RNA, Small Interfering / genetics
  • Receptor, Notch1 / genetics
  • Repressor Proteins
  • Splicing Factor U2AF / genetics*
  • Transcriptome
  • Ubiquitin Thiolesterase / genetics*

Substances

  • Carrier Proteins
  • Codon, Nonsense
  • F-Box-WD Repeat-Containing Protein 7
  • Fbxw7 protein, mouse
  • MED12 protein, human
  • Mediator Complex
  • NOTCH1 protein, human
  • Nuclear Proteins
  • PHF6 protein, human
  • RNA, Small Interfering
  • Receptor, Notch1
  • Repressor Proteins
  • Splicing Factor U2AF
  • U2AF1 protein, human
  • USP9X protein, human
  • Histone Demethylases
  • KDM6A protein, human
  • JAK1 protein, human
  • JAK3 protein, human
  • Janus Kinase 1
  • Janus Kinase 3
  • Ubiquitin Thiolesterase