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In Vitro Sensitivity of T-Cell Lymphoblastic Leukemia to UCN-01 (7-Hydroxystaurosporine) Is Dependent on p16 Protein Status: A Pediatric Oncology Group Study¹

Department of Pediatrics/Hematology-Oncology, University of California, San Diego, California 92103 [M. O-M., M. B. D., A. B., R. C. C., L. J. B., E. d. W., F. H. K., A. L. Y.]; The Scripps Research Institute, La Jolla, California 92037 [J. Y.]; and Division of Pediatric Hematology Oncology, The University of Mississippi, Jackson, Mississippi 39216 [J. D. P.]

p16 regulates the cell cycle pathway by inhibiting the cyclin Ds-cyclin-dependent kinase (CDK) 4/6-mediated phosphorylation of retinoblastoma protein (pRb). Previously, we reported that most primary T-cell acute lymphoblastic leukemia (T-ALL) harbored p16 inactivation and hyperphosphorylated pRb without cyclin Ds or CDK4/6 alterations. Therefore, inhibiting CDK4/6 may be an ideal therapeutic approach for p16 (-) T-ALL. UCN-01 (7-hydroxystaurosporine) is a potent antitumor agent that exerts its effects through the inhibition of CDKs. We now report that p16 protein expression status of T-ALL cells influences their sensitivity to UCN-01. In 36 primary T-ALL cells, the IC₅₀s of UCN-01 in the 27 p16 (-) cells (43 ± 52 nM) was significantly lower than that in the 9 p16 (+) cells (258 ± 260 nM). Our results suggest that agents like UCN-01 may be useful as a p16-selective therapy for T-ALL.

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