INFREQUENT ALTERATIONS OF THE RAR-ALPHA GENE IN ACUTE MYELOGENOUS LEUKEMIAS, RETINOIC ACID-RESISTANT ACUTE PROMYELOCYTIC LEUKEMIAS, MYELODYSPLASTIC SYNDROMES, AND CELL-LINES

Retinoids are important regulators of cell growth and differentiation in vitro and in vivo and they exert their biologic activities by bindi ng to nuclear retinoic acid receptors (RARs; alpha, beta, and gamma) a nd retinoid X receptors (RXRs; alpha, beta, and gamma). All-trans reti noic acid (RA) induces complete remission in patients with acute promy elocytic leukemia (APL) presumably by binding directly to RAR alpha of APL cells. Leukemic blasts from APL patients initially responsive to RA can become resistant to the agent. HL-60 myeloblasts cultured with RA have developed mutations of the ligand-binding region of RAR alpha and have become resistant to RA. Furthermore, insertion of an RAR alph a with an alteration in the ligand-binding region into normal murine b one marrow cells can result in growth factor-dependent immortalization of the early hematopoietic cells. To determine if alterations of the ligand binding domain of RAR alpha might be involved in several malign ant hematologic disorders, the mutational status of this region (exons 7, 8, and 9) was examined in 118 samples that included a variety of c ell lines and fresh cells from patients with myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), including 20 APL patients, 5 of whom were resistant to RA and 1 who was refractory to RA at diagno sis, using polymerase chain reaction-single-strand conformational poly morphism (PCR-SSCP) analysis and DNA sequencing. In addition, 7 of the 20 APLs were studied for alterations of the other coding exons of the gene (exons 2 through 6). No mutations of RAR alpha were detected. Al though the sensitivity of PCR-SSCP analysis is less than 100%, these f indings suggest that alterations of RAR alpha gene are rare and theref ore other mechanisms must be involved in the onset of resistance to re tinoids and in the lack of differentiation in disorders of the myeloid lineage. (C) 1996 by The American Society of Hematology.