Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 1047-1055
Regulation of drug sensitivity by ribosomal protein S3a
Z.-B. Hu,
M. D. Minden, and
E. A. McCulloch
From the Ontario Cancer Institute/Princess Margaret Hospital,
Toronto, Canada.
When bcl-2 is immunoprecipitated from 32P-labeled cell
extracts of all-trans retinoic acid (ATRA)-treated acute
myeloblastic leukemia (AML) blasts, a phosphorylated protein of
approximately 30 kd is coprecipitated. This protein has been identified
as ribosomal protein S3a. The biologic effects of S3a include favoring
apoptosis and enhancing the malignant phenotype. We sought to determine whether S3a, like bcl-2, influenced the response of cells to
chemotherapeutic drugs and ATRA. Cell lines were studied in which S3a
was genetically increased or disrupted; increased S3a was regularly
associated with increased plating efficiency and increased sensitivity
to either cytosine arabinoside (ara-C) or doxorubicin (DNR). S3a did
not affect the sensitivity of cells to paclitaxel. Pulse
exposures to either 3HTdR 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 S3a
responded to ATRA by increased ara-C or DNR sensitivity, whereas cells
with reduced S3a protein were either protected by ATRA or not affected.
We studied cryopreserved blast cells from patients with AML or chronic
myelomonocytic leukemia (CMML). S3a protein levels were heterogeneous
in these populations. In 32 cryopreserved blast populations, S3a levels
were significantly correlated with both bcl-2 and with cell growth in
culture. As in cell lines, high S3a in cryopreserved blasts was
associated with ATRA-induced sensitization to ara-C. No significant
association was seen between S3a levels and response to treatment.
