Unité INSERM U417, Hôpital Saint Antoine, Paris, France

Correspondence to: P G Lutz, Unité INSERM U417, Hôpital Saint Antoine, 184 Rue du Faubourg Saint Antoine, 75012 Paris, France; Fax: 33-1-43406837

Although transcription factors are still the main focus to understanding leukemogenesis, recent results strongly suggest that alteration of a receptor and/or subsequent signaling plays a critical and co-operative role in the pathogenesis of acute myeloid leukemia (AML). The t(15;17) translocation, found in 95% of APL, encodes a PML-RAR fusion protein. A main model proposed for acute promyelocytic leukemia (APL) is that PML-RAR exerts its oncogenic effects by repressing retinoic acid-inducible genes critical to myeloid differentiation. Dysregulation of these genes may result in abnormal signaling, thereby freeing pre-leukemic cells from controls which normally induce the onset of differentiation. It is also likely that treatment of APL cells by retinoic acid induces de novo up-regulation of the same genes which are dominantly repressed by PML-RAR and whose expression is required for reactivation of the differentiation program. Identification of such genes together with the signaling pathways interrupted at the early stages of leukemia transformation and reactivated during retinoic acid-induced differentiation in APL cells will contribute to the development of new molecular targets for treatment of leukemia.

Leukemia (2002) 16, 1933-1939. doi:10.1038/sj.leu.2402728

Keywords: APL; retinoids; differentiation; growth-arrest; adaptor; signal transduction