Fusion with E2A alters the transcriptional properties of the homeodomain protein PBX1 in t(1;19) leukemias.
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.
LeBrun
D P
DP
Department of Pathology, Stanford University Medical Center, California 94305.
Cleary
M L
ML
D001483:Base Sequence; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008969:Molecular Sequence Data; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D015533:Transcriptional Activation; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C083400:PBX1 protein, human; D004247:DNA