The retinoic acid receptor alpha gene is rearranged in retinoic acid-sensitive promyelocytic leukemias

Abstract : All-trans retinoic acid (RA), the active metabolite of vitamin A, has recently been demonstrated to be an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (M3 subtype of the French-American-British cytological classification). Complete remission is obtained by inducing terminal granulocytic differentiation of the leukemic cells. To elucidate whether the effect of retinoic acid on the differentiation of M3 leukemic cells was related to any specific characteristics of its receptor, we analyzed the structure and expression of retinoic acid receptor (RAR) genes in 16 M3 patients. Abnormal RAR alpha transcripts were detected in 13 cases. In nine patients, the genomic DNA was analyzed by Southern blotting and evidence for a rearranged RAR alpha gene was found generated in four cases. Normal RAR transcripts and germline restriction fragments were found in samples from normal or other leukemic cells, suggesting that this alteration of the RAR alpha gene is specifically seen in M3 leukemias. These results suggest that alteration of the retinoic acid receptor alpha may be implicated in M3 leukemogenesis.