A proposed model of blast crisis of chronic myeloid leukemia as a DNA repair disorder

Y Maru, MD, PhD

Institute of Medical Science, University of Tokyo, Tokyo, Minato-ku Japan

We are aimed at searching molecules by which to explain genomic instability in chronic myeloid leukemia (CML). The Dbl-homology (DH) domain of CML-specific P210BCR-ABL was used as a bait to isolate binding proteins in yeast two-hybrid system. The genotoxin-sensitive 27-1 cell system was utilized to assay DNA repair potentials of transfected genes, and was subjected to differential display analysis. Yeast two-hybrid screening gave the XPB gene whose product binds specifically to the DH domain of BCR but not of other Dbl family members. Coexpression of P210BCR-ABL and XPB in 27-1 cells (27-1/XPB/P210) counteracted against the repair-correcting ability of XPB. Although the helicase activity of P210-bound XPB was inhibited at least in vitro, a low stoichiometry of P210 binding to XPB in vivo, a high anti-repair activity of P210 in 27-1 cell system, and a change of in vitro transcription activity of TFIIH purified from 27-1/XPB/P210 cells prompted us to perform differential display analysis. PO, a ribosomal protein with AP-endonuclease activity, was found to be one of the genes whose expression level correlated with sensitivity to genotoxins. PO was detected in anti-XPB immune complex, and its expression in 27-1 cells enhanced the repair activity against methylmethane sulfonate and hydrogen peroxide. Anti-repair effect of BCR-ABL may be caused in part by transcriptional changes of repair genes such as PO.

KEY WORDS: DNA repair, .

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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 Gene Expression, Part 2.