Retinoid receptor expression and its correlation to retinoid sensitivity in non-M3 acute myeloid leukemia blast cells.
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 alpha, RAR beta, RAR gamma, and RXR alpha 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 alpha and RXR alpha and low expression of RAR beta and RAR gamma. 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 alpha, RAR beta, RAR gamma, and RXR alpha in 46%, 77%, 30%, and 38% of the samples, respectively. The mean increase in receptor expression was most pronounced for RAR beta and RXR alpha. There was a significant correlation between an increase in RAR beta expression in response to ATRA and sensitivity to ATRA (P < 0.014). No such correlations were found for RAR alpha, RAR gamma, and RXR alpha. The expression of the monocytoid marker CD14 was significantly correlated with increased expression of RAR alpha (P = 0.03). We conclude that RAR alpha, RAR beta, RAR gamma, and RXR alpha are expressed in non-M3 AML blast cells and that ATRA-induced expression of RAR beta may be a marker for retinoid sensitivity.
Department of Hematology, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden. Soren.Lehmann@medhs.ki.se
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D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D017931:DNA Primers; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014212:Tretinoin