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Constitutive Expression of Cellular Retinoic Acid Binding Protein II and Lack of Correlation with Sensitivity to All-Trans Retinoic Acid in Acute Promyelocytic Leukemia Cells¹

Department of Oncology, Montefiore Medical Center and Albert Einstein Cancer Center, Bronx, New York 10467 [D-C. Z, S. J. H., R. S. K., P. H. W., R. E. G.]; Division of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [S. J. L.]; and Division of Hematology/Oncology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois 60611 [M. S. T.], with the Eastern Cooperative Oncology Group, Brookline, Massachusetts 02146

The up-regulation of cellular retinoic acid binding protein-II (CRABP-II) has been invoked as an important mechanism of clinically acquired resistance to all-trans retinoic acid (RA) therapy in acute promyelocytic leukemia (APL). To test this hypothesis, we used quantitative reverse transcription-PCR and fast performance liquid chromatography procedures to examine the levels of CRABP-II mRNA and RA binding activity in APL patient samples. We found that CRABP-II mRNA in APL cells from pretreatment patients (n = 36) was constitutively expressed at relatively high levels (median, 0.92; range, 0.16–4.13) relative to the level in CRABP-II protein-expressing NB4 cells (arbitrarily set at 1.0 unit). Consistent with this finding, the RA binding activity of CRABP in APL cells from three pretreatment cases (range, 27.2–53.2 fmol/mg protein) was similar to that of NB4 cells (22.6 ± 5.4 fmol/mg protein). Furthermore, in the pretreatment samples, there was no association between CRABP-II mRNA expression level and APL cellular sensitivity to RA-induced differentiation in vitro. After 45 days of remission induction therapy on Eastern Cooperative Oncology Group protocol E2491, CRABP-II mRNA was modestly increased from day 0 values in patients treated with either RA (median increase, 0.41) or chemotherapy (median increase, 0.56), and there was no significant difference between the two treatment groups (P = 0.91). In patients studied after relapse from RA therapy (n = 7), there was a significant decline in APL cell sensitivity to RA-induced differentiation in vitro compared with patients after relapse from chemotherapy (n = 5; P = 0.015-0.055 at three RA concentrations tested), but in the RA relapse cases, there was no change from pretreatment levels of CRABP-II mRNA (median, 0.98) or, in three relapse cases studied, of RA protein binding activity (range, 22.1–70.7 fmol/mg protein). Taken together, our data strongly imply that variations in CRABP-II expression and RA binding activity are not causally related to the development of clinically acquired APL cellular RA resistance, but rather, they suggest that constitutive expression of CRABP-II could have a facilitative role in the response of APL cells to RA.

¹ This work was supported by USPHS Grant CA 56771 (to R. E. G.). This study was in the majority based on protocol E2491, "Phase III Randomized Study of All-trans Retinoic Acid versus 1-ß-D-Arabinofuranosylcytosine and Daunomycin for Patients with Previously Untreated Acute Promyelocytic Leukemia," conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair).

² To whom requests for reprints should be addressed, at Department of Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, 11 East 210th Street, Bronx, NY 10467. Phone: (718) 920-4186; Fax: (718) 798-7474.

Received 7/ 7/98. Accepted 10/14/98.

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