ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation

Nat Commun. 2016 Jun 2;7:11733. doi: 10.1038/ncomms11733.

Abstract

The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 21 / chemistry
  • Chromosomes, Human, Pair 21 / metabolism
  • Chromosomes, Human, Pair 8 / chemistry
  • Chromosomes, Human, Pair 8 / metabolism
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic*
  • Glycolysis / genetics
  • HEK293 Cells
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Mutation*
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Protein Domains
  • RUNX1 Translocation Partner 1 Protein / genetics*
  • RUNX1 Translocation Partner 1 Protein / metabolism
  • Signal Transduction
  • Survival Analysis
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Translocation, Genetic*

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1 protein, human
  • RUNX1T1 protein, human
  • Transcription Factors
  • ZBTB7A protein, human