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Molecular and Cellular Biology, September 2006, p. 6442-6452, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.02025-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Critical Role for a Single Leucine Residue in Leukemia Induction by E2A-PBX1

Richard Bayly,1 Takayuki Murase,1 Brandy D. Hyndman,1 Rachel Savage,1 Salima Nurmohamed,1,2 Kim Munro,2 Richard Casselman,1 Steven P. Smith,2 and David P. LeBrun1*

Queen's University Cancer Research Institute, Department of Pathology and Molecular Medicine,1 Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada2

Received 17 October 2005/ Returned for modification 16 December 2005/ Accepted 21 June 2006

In roughly 5% of cases of acute lymphoblastic leukemia, a chromosomal translocation leads to expression of the oncogenic protein E2A-PBX1. The N-terminal portion of E2A-PBX1, encoded by the E2A gene, is identical in sequence to the corresponding portion of the E proteins E12/E47 and includes transcriptional activation domains. The C terminus consists of most of the HOX interacting transcription factor PBX1, including its DNA-binding homeodomain. Structure-function correlative experiments have suggested that oncogenesis by E2A-PBX1 requires an activation domain, called AD1, at the extreme N terminus. We recently demonstrated that a potentially helical portion of AD1 interacts directly with the transcriptional coactivator protein cyclic AMP response element-binding protein (CBP) and that this interaction is essential in the immortalization of primary bone marrow cells in tissue culture. Here we show that a conserved LXXLL motif within AD1 is required in the interaction between E2A-PBX1 and the KIX domain of CBP. We show by circular dichroism spectroscopy that the LXXLL-containing portion of AD1 undergoes a helical transition upon interacting with the KIX domain and that amino acid substitutions that prevent helix formation prevent both the KIX interaction and cell immortalization by E2A-PBX1. Perhaps most strikingly, substitution of a single, conserved leucine residue (L20) within the LXXLL motif impairs leukemia induction in mice after transplantation with E2A-PBX1-expressing bone marrow. The KIX domain of CBP mediates well-characterized interactions with several transcription factors of relevance to leukemia induction. Circumstantial evidence suggests that the side chain of L20 might interact with a deep hydrophobic pocket in the KIX domain. Therefore, our results serve to identify a potential new drug target.

* Corresponding author. Mailing address: Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario K7L 3N6, Canada. Phone: (613) 533-3209. Fax: (613) 533-6830. E-mail: lebrun{at}cliff.path.queensu.ca.

Molecular and Cellular Biology, September 2006, p. 6442-6452, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.02025-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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  • Bhalla, S., Spaulding, C., Brumbaugh, R. L., Zagort, D. E., Massari, M. E., Murre, C., Kee, B. L. (2008). Differential Roles for the E2A Activation Domains in B Lymphocytes and Macrophages. J. Immunol. 180: 1694-1703 [Abstract] [Full Text]  


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