AM580, A STABLE BENZOIC DERIVATIVE OF RETINOIC ACID, HAS POWERFUL ANDSELECTIVE CYTO-DIFFERENTIATING EFFECTS ON ACUTE PROMYELOCYTIC LEUKEMIA-CELLS

All-trans retinoic acid (ATRA) is successfully used in the cyto-differ entiating treatment of acute promyelocytic leukemia (APL). Paradoxical ly, APL cells express PML-RAR, an aberrant form of the retinoic acid r eceptor type alpha (RAR alpha) derived from the leukemia-specific t(15 ;17) chromosomal translocation. We show here that AM580, a stable reti nobenzoic derivative originally synthesized as a RAR alpha agonist, is a powerful inducer of granulocytic maturation in NB4, an APL-derived cell line, and in freshly isolated APL blasts, After treatment of APL cells with AM580 either alone or in combination with granulocyte colon y-stimulating factor (G-CSF), the compound induces granulocytic matura tion, as assessed by determination of the levels of leukocyte alkaline phosphatase, CD11b, CD33, and G-CSF receptor mRNA, at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects. By contrast, AM580 is not so effective as ATRA in mo dulating the expression of these differentiation markers in the HL-60 cell line and in freshly isolated granulocytes obtained from the perip heral blood of chronic myelogenous leukemia patients during the stable phase of the disease. In NB4 cells, two other synthetic nonselective RAR ligands are capable of inducing LAP as much as AM580, whereas RAR beta- or RAR gamma-specific ligands are totally ineffective. These res ults show that AM580 is more powerful than ATRA in modulating the expr ession of differentiation antigens only in cells in which PML-RAR is p resent. Binding experiments, using COS-7 cells transiently transfected with PML-RAR and the normal RAR alpha, show that AM580 has a lower af finity than ATRA for both receptors. However, in the presence of PML-R AR, the synthetic retinoid is a much better transactivator of retinoic acid-responsive element-containing promoters than the natural retinoi d, whereas, in the presence of RAR alpha, AM580 and ATRA have similar activity. This may explain the strong cyto-differentiating potential o f AM580 in PML-RAR-containing leukemic cells. (C) 1996 by The American Society of Hematology.