Format

Send to

Choose Destination
Sci Rep. 2019 Mar 20;9(1):4915. doi: 10.1038/s41598-019-41393-w.

Oligomeric self-association contributes to E2A-PBX1-mediated oncogenesis.

Author information

1
Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
2
Sun Yat-Sen University, School of Pharmaceutical Sciences, Guangzhou, 510006, China.
3
Department of Hematology and Oncology, University Medical Center Freiburg, Freiburg, Germany.
4
Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
5
Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, M20 4GJ, UK.
6
Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA. mcleary@stanford.edu.

Abstract

The PBX1 homeodomain transcription factor is converted by t(1;19) chromosomal translocations in acute leukemia into the chimeric E2A-PBX1 oncoprotein. Fusion with E2A confers potent transcriptional activation and constitutive nuclear localization, bypassing the need for dimerization with protein partners that normally stabilize and regulate import of PBX1 into the nucleus, but the mechanisms underlying its oncogenic activation are incompletely defined. We demonstrate here that E2A-PBX1 self-associates through the PBX1 PBC-B domain of the chimeric protein to form higher-order oligomers in t(1;19) human leukemia cells, and that this property is required for oncogenic activity. Structural and functional studies indicate that self-association facilitates the binding of E2A-PBX1 to DNA. Mutants unable to self-associate are transformation defective, however their oncogenic activity is rescued by the synthetic oligomerization domain of FKBP, which confers conditional transformation properties on E2A-PBX1. In contrast to self-association, PBX1 protein domains that mediate interactions with HOX DNA-binding partners are dispensable. These studies suggest that oligomeric self-association may compensate for the inability of monomeric E2A-PBX1 to stably bind DNA and circumvents protein interactions that otherwise modulate PBX1 stability, nuclear localization, DNA binding, and transcriptional activity. The unique dependence on self-association for E2A-PBX1 oncogenic activity suggests potential approaches for mechanism-based targeted therapies.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center