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by Nicole Panucci MD/Ph.D. Program B.A. 2003, Rice University Thesis Advisor: Ian Whitehead, Ph.D. Associate Professor Department: Microbiology and Molecular Genetics Cancer Center G 1196 Wednesday, April 22, 2009 1:00 pm Abstract The p210 BCR/ABL fusion protein is causally associated with virtually all cases of chronic myelogenous leukemia (CML). Previous studies have demonstrated that p210 BCR/ABL interacts directly with the xeroderma pigmentosum group B (XPB) protein and that the docking site resides within the BCR component. In the current study we have constructed a p210 BCR/ABL mutant that can no longer bind to XPB. The mutant has normal kinase activity, and interacts with GRB2, but can no longer phosphorylate XPB. When compared to myeloid cells that express p210 BCR/ABL, cells that express the mutant still exhibit interleukin-3 (IL-3) independent growth, but show reduced resistance to ultraviolet C (UVC)-induced apoptosis. When examined in a bone marrow transplantation (BMT) model for CML, mice that express the mutant exhibit myeloproliferation, but show no evidence of lymphoproliferation, and have significantly extended lifespans relative to those that express unmodified p210 BCR/ABL. This was confirmed in a BMT model for B cell acute lymphoblastic leukemia (B-ALL) where the majority of the mutant transplanted mice remained disease free. These results suggest that the interaction between p210 BCR/ABL and XPB may contribute to disease progression by supporting the expansion of the lymphoid compartment. |
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