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Retinoid Receptor Expression and Its Correlation to Retinoid Sensitivity in Non-M3 Acute Myeloid Leukemia Blast Cells¹

Department of Hematology, Karolinska Institute, Huddinge Hospital, 141 86 Stockholm, Sweden [S. L., C. P.], and Department of Medical Sciences, Section of Dermatology and Venereology, University of Uppsala, 75185 Uppsala, Sweden [H. T.]

All-trans-retinoic acid (ATRA) has significantly improved the treatment results in acute promyelocytic leukemia (M3). In non-M3 acute myeloid leukemia (AML), the effects are less clear, and there is a pronounced heterogeneity in the sensitivity to the growth-inhibitory effects of retinoids in leukemic cells from different non-M3 AML patients. Retinoids exert their effects through a number of nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)]. In this study, we determined the expression of RAR, RARß, RAR, and RXR by real-time PCR in four cell lines and in blast cells from patients with non-M3 AML before and after ATRA incubation. All four receptors were expressed in cells from all 18 tested patient samples and in four myeloid cell lines. In the majority of the patient samples as well as in the cell lines, there was a pattern of high expression of RAR and RXR and low expression of RARß and RAR. There was no correlation between the basal expression of any of the retinoid receptors and sensitivity to ATRA. A 24-h exposure to ATRA increased the expression of RAR, RARß, RAR, and RXR in 46%, 77%, 30%, and 38% of the samples, respectively. The mean increase in receptor expression was most pronounced for RARß and RXR. There was a significant correlation between an increase in RARß expression in response to ATRA and sensitivity to ATRA (P < 0.014). No such correlations were found for RAR, RAR, and RXR. The expression of the monocytoid marker CD14 was significantly correlated with increased expression of RAR (P = 0.03). We conclude that RAR, RARß, RAR, and RXR are expressed in non-M3 AML blast cells and that ATRA-induced expression of RARß may be a marker for retinoid sensitivity.

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