Biological features of primary APL blasts: their relevance to the understanding of granulopoiesis, leukemogenesis and patient management Bruno Cassinat 1 and Christine Chomienne* ,1 1 Hopital Saint-Louis, Paris, Institute of Hematology, INSERM E 00-03 France In recent years, discovery of the in vitro and in vivo dierentiation of APL blasts by all-trans retinoic acid (ATRA) has modi®ed the therapeutic approach of APL and lead to important advances in understanding the biology of APL. Since it became apparent that dierentiation therapy of APL with ATRA was indeed a true model of targetted therapy, evidencing the molecular targets of retinoic acid ecacy became crucial. These molecular targets are closely related to the biological features of APL cells, some of which are well-known and have contributed to the morphological and cytogenetic de®nition of the leukemia, others have just been de®ned or re-discovered in the light of a better understanding of molecular controls of cell growth and dierentiation. The aims of characterizing the biological features of APL cells should allow a better management of APL therapy and the identi®ca- tion of potential markers for dierentiation therapies in other leukemias or solid tumors. Oncogene (2001) 20, 7154 ± 7160. Keywords: APL blasts; dierentiation; granulopoiesis; retinoids; RARa gene rearrangements Introduction Acute promyelocytic leukemia (APL) is a morpho- logically, cytogenetically and clinically distinct sub- type of acute myeloid leukemia (AML3) characterized by the morphology of the blast cells, a speci®c t(15;17) translocation and risks of coagulopathy (Bennett et al., 1976). This leukemia was further characterized by an exquisite sensitivity to all-trans retinoic acid (ATRA) and the production of a fusion gene altering the RARa and PML genes (for review Grignani et al., 1994). Other features have been described, (previously or more recently) such as variations in the cytological or immunophenotypic aspect, or novel cytogenetic and oncogenic markers. Analysis of these subtle aspects of APL are being analysed at the European and International level to de®ne whether these novel features de®ne dierent sub-groups of a same leukemia or represent distinct leukemic entities (Sainty et al., 2000; Grimwade et al., 2000) To date, no other AML subtype responds to ATRA, con®rming that dierentiation therapy of APL with ATRA is indeed a true model of targetted therapy. Thus, evidencing the molecular targets of retinoic acid ecacy is crucial. These molecular targets are closely related to the biological features of APL cells, some of which are well-known and have contributed to the morphological and cytogenetic de®nition of the leukemia, and the discovery of its sensitivity to ATRA (morphological criteria, t(15;17) translocation and/or PML ± RARa expression); others have just been de®ned or re-discovered either in the light of a better understanding of molecular controls of cell growth and dierentiation or of retinoic acid signaling pathways. We have recently evidenced that relapse rate of APL patients is determined by the sensitivity of the APL clone to ATRA at diagnosis (Cassinat et al., 2001). If the aim of dierentiation therapy is to increase survival and achieve a cure of the disease, knowledge of the dierent biological features of the various APLs should allow a better targetting of APL therapy and might be transposed to other dieren-tiation therapies in leukemias or solid tumors. Normal myeloid features of the APL cell In vitro differentiation of APL cells with ATRA, a model for normal granulocytic differentiation Altered RARa receptors block normal granulocytic dierentiation and arrest cells at the promyelocytic stage of myeloid dierentiation (Collins et al., 1990; Parrado et al., 2000). APL, which is induced by a variety of chromosomal translocations into the retinoic acid receptor gene, are recognized cytologically by their resemblance to a promyelocyte. Apart from a speci®c nucleus conformation and characteristic aspect of the chromatin, the promyelocyte is characterized by `primary' azurophilic granules that persist in decreas- ing numbers until the last phases of neutrophil maturation. These granules contain proteases (the group of Cathepsin G, Leucocyte Elastase and Oncogene (2001) 20, 7154 ± 7160 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc *Correspondence: C Chomienne, INSERM E 00-03 Laboratoire de Biologie Cellulaire HeÂmatopoõÈeÂtique, Institut d'HeÂmatologie, HoÃpital Saint-Louis, 1 avenue Claude Vellefaux 75010 Paris, France