Patients with chronic myelogenous leukemia (CML) typically carry a balanced reciprocal translocation between chromosomes 9 and 22, resulting in the production of an in-frame fusion protein known as p210 BCR/ABL. Expression of p210 BCR/ABL in myeloid cells is associated with a variety of transformed cellular phenotypes including changes in nucleotide excision repair (NER). Consistent with this, previous studies have demonstrated that p210 BCR/ABL interacts directly with xeroderma pigmentosum group B (XPB), a protein necessary for both transcription and NER. In the current study we have mapped the docking site for XPB within the RhoGEF domain of BCR, and have constructed a p210 BCR/ABL mutant that is deficient in XPB binding. The mutant has normal kinase activity, and retains Grb2 binding ability, but can no longer phosphorylate XPB. When expressed in 32Dc13 cells, the mutant still confers IL-3 independent growth, but abrogates the resistance to ultraviolet C (UVC)-induced apoptosis seen in wild-type p210 BCR/ABL expressing cells. In a bone marrow transplantation model for CML, mice that express the mutant have significantly extended lifespans. Whereas p210 BCR/ABL transplanted mice became moribund within 28–35 days of transplantation, mutant mice survived for an average of 78 days. Necropsies performed at death revealed splenomegaly and clear evidence of myeloproliferation in the mutant mice, however tissue infiltration and lung hemorrhage was less extensive than in the p210 BCR/ABL expressing mice. These results suggest that the interaction between p210 BCR/ABL and XPB regulates disease progression, and may represent a novel target for therapeutic intervention.

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