Acute promyelocytic leukemia: from genetics to treatment.

A CUTE PROMYELOCYTIC leukemia (APL) has aroused interest well beyond the hematologic field during the last 4 to 5 years. Two features, both of which are unique to APL, have attracted the attention of various sectors of biomedical research: (1) the remission of the disease obtained with retinoic acid (RA) treatment, whose mechanism of action consists in inducing the APL blasts to differentiate term in all^"^; and (2) the presence in the APL blasts of an anomalous protein, the PML/RARa protein, a mutant of one of the retinoic acid receptor^.^-^ The high sensitivity of the promyelocytic blasts to RA makes APL a unique model for differentiation therapy. Because this antineoplastic strategy is radically different from conventional cytotoxic chemotherapy, it potentially provides a further tactic for controlling neoplastic growth. Several attempts were made to treat hematologic neoplastic disorders with differentiation therapy in the past.’ They were based on the observation that the differentiation block is a striking feature of the leukemic phenotype* and that it can be reversed in vitro by a number of substances (eg, low-dose Ara-C).’ Unfortunately, on the whole, these clinical trials led to disappointing results.” In contrast, differentiation therapy with RA induces clinical remission in the great majority of APL patient^."^ The PML/RARa fusion protein is formed as the consequence of a chromosomal translocation, [t( 15; 17)] that involves the PML and RARa genes.4s5 The anomalous protein is thought to play a crucial role in promyelocytic leukemogenesis. RARa is a member of the super-family of nuclear hormone receptors that are involved in fundamental biologic processes such as development and differentiation.” The discovery of a putative oncogenic RARa mutant, PML/RARa, raises questions of great importance concerning the normal function and oncogenic potential of all members of the nuclear receptor super-family. The association of these two unique features of APL is paradoxical. On one hand, the alteration in the RA signaling pathway by PML/RARa could contribute to the leukemic