Regulation of drug sensitivity by ribosomal protein S3a

When bcl-2 is immunoprecipitated from P-32-labeled cell extracts of all-tra ns retinoic acid (ATRA)-treated acute myeloblastic leukemia (AML) blasts, a phosphorylated protein of approximately 30 kd is coprecipitated, This prot ein has been identified as ribosomal protein S3a, The biologic effects of S 3a include favoring apoptosis and enhancing the malignant phenotype. We sou ght to determine whether S3a, like bcl-2, influenced the response of cells to chemotherapeutic drugs and ATRA. Cell lines were studied in which S3a wa s genetically increased or disrupted; increased S3a was regularly associate d with increased plating efficiency and increased sensitivity to either cyt osine arabinoside (ara-C) or doxorubicin (DNR), S3a did not affect the sens itivity of cells to paclitaxel, Pulse exposures to either (3)HTdR or ara-C showed a greater percentage of clonogenic cells in the S phase of the cell cycle in cells with increased S3a than in controls. Cells with increased S3 a responded to ATRA by increased ara-C or DNR sensitivity, whereas cells wi th reduced S3a protein were either protected by ATRA or not affected. We st udied cryopreserved blast cells from patients with AML or chronic myelomono cytic leukemia (CMML), S3a protein levels were heterogeneous in these popul ations. In 32 cryopreserved blast populations, S3a levels were significantl y correlated with both bcl-2 and with cell growth in culture. As in cell li nes, high S3a in cryopreserved blasts was associated with ATRA-induced sens itization to ara-C, No significant association was seen between S3a levels and response to treatment. (C) 2000 by The American Society of Hematology.