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Thioredoxin Expression in Primary T-Cell Acute Lymphoblastic Leukemia and Its Therapeutic Implication¹

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037 [L. S., T. T., R. G., J. Y.]; Department of Pediatrics, University of California at San Diego Medical Center, San Diego, California 92103 [M. B. D., A. L. Y.]; University of Mississippi Medical Center, Jackson, Mississippi 39216 [J. D. P.]; and Midwest Children’s Cancer Center, Milwaukee, Wisconsin 53226 [B. M. C.]

Increased expression of intracellular thioredoxin has been implicated in the inhibition of apoptosis and in a decrease in the sensitivity of the malignancies to drug-induced apoptosis. In the present studies, we analyzed expression of thioredoxin in samples from 28 children with T-cell acute lymphoblastic leukemia and analyzed their sensitivity toward inhibition of thioredoxin expression. Thioredoxin was expressed in variable amounts. Higher expression was associated with higher WBC counts. Exogenously added thioredoxin stimulated proliferation of clonogenic cells among the T-cell acute lymphoblastic leukemia samples expressing relatively lower levels of intracellular thioredoxin, whereas there was no effect on the clonogenic cells expressing high levels of thioredoxin. In addition, there was differential sensitivity of the leukemia clonogenic cells toward 1-methylpropyl 2-imidazolyl disulfide, an inhibitor of thioredoxin expression, as compared with normal hematopoietic progenitors. This suggests the possibility of using this approach for treatment. Because overexpression of thioredoxin is associated with resistance to many anticancer drugs, the inhibition of thioredoxin expression may overcome this drug resistance and probably sensitize leukemia cells to other chemotherapeutic agents.

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