Fusion with E2A alters the transcriptional properties of the homeodomain protein PBX1 in t(1;19) leukemias

Oncogene. 1994 Jun;9(6):1641-7.

Abstract

The t(1;19) chromosomal translocation is observed in pre-B cell acute lymphoblastic leukemias and results in expression of chimeric E2A-PBX1 proteins that contain transcriptional activation domains from E2A and the homeodomain of PBX1. Since homeodomains mediate DNA-binding, a potential model for the action of E2A-PBX1 is that it disrupts the transcriptional regulation of genes normally controlled by PBX1 or its closely-related family members PBX2 or PBX3. Using a binding site selection assay, we identified a consensus nucleotide sequence ATCAATCA specifically bound by the PBX1 homeodomain and those of its closely-related family members PBX2 and PBX3. An endogenous protein with the properties of PBX3b specifically bound to this sequence in nuclear extracts of precursor B cells. Transfection of reporter genes containing PBX binding sites linked to a minimal promoter demonstrated transactivation by E2A-PBX1 fusion protein dependent upon presence of the homeodomain. In contrast, wild-type PBX proteins were incapable of activating transcription. The striking differences in transcriptional properties of fusion and wild-type PBX proteins provides strong functional evidence for the importance of aberrant transcriptional regulation in the genesis of t(1;19)-bearing leukemias.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Chromosomes, Human, Pair 1
  • Chromosomes, Human, Pair 19
  • DNA / metabolism
  • DNA-Binding Proteins / physiology*
  • Humans
  • Leukemia / genetics*
  • Molecular Sequence Data
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Proto-Oncogene Proteins / physiology*
  • Recombinant Fusion Proteins / physiology*
  • TCF Transcription Factors
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factors*
  • Transcriptional Activation*
  • Translocation, Genetic*

Substances

  • DNA-Binding Proteins
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • TCF Transcription Factors
  • TCF7L1 protein, human
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factors
  • PBX1 protein, human
  • DNA