Bcr: A negative regulator of the Bcr-Abl oncoprotein

RB ArlinghausPhD, T Sun, J Liu, W Fang, Y Wang

Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030

AIM: To define the role of the Bcr protein in leukemia caused by the Bcr-Abl oncoprotein. The hypothesis: a phosphoserine form of the Bcr protein antagonizes the oncogenic effects of the Bcr-Abl oncoprotein. METHODS: Involves studies with cells derived from chronic myelogenous leukemia patients and normal controls. Two animal models for leukemia are being studied: NOD/scid mice allows engraftment of human leukemia cells; and a bone marrow transplant model in which marrow cells from Balb/c mice are infected with a retrovirus encoding the BCR-ABL oncogene and a green fluorescent protein gene (GFP). RESULTS: Our previous studies have established that sequences within the first exon of the BCR gene inhibit the oncogenic activity of the Bcr-Abl oncoprotein (Cancer Res. 56:5120, 1996; 61:138, 2001). These studies were performed with a mutant BCR, encoding residues 63-413 of the Bcr protein. Later studies revealed that the full length Bcr protein also antagonizes the Bcr-Abl oncoprotein (Oncogene 18:4416, 1999). We tested the effects of inducible BCR gene expression in a leukemia patient cell line (K562 cells). Repression of BCR expression resulted in 100% lethality in the NOD/scid mouse model (Oncogene 20:1873, 2001). Induction of BCR expression prevented leukemia in 80% of the mice. We have investigated the mechanism of action of Bcr's inhibition of this leukemia. Our findings indicate that a unique phosphoserine form of Bcr binds tightly to the SH2 domain of the Bcr-Abl oncoprotein. As phosphotyrosine sequences normally bind to SH2 domains, we predict that the binding of phosphoserine Bcr perturbs the tyrosine kinase catalytic domain of Bcr-Abl, causing kinase inhibition, leading to the reversal of the leukemia process induced by Bcr-Abl. Molecular mechanism studies concerning the novel binding of phosphoserine Bcr to the SH2 domain are underway.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Chromosomal Aberrations.