Retinoid receptors and acute promyelocytic leukaemia.

While a great deal has been learned about APL over the last few years, many important questions remain unanswered. It has become clear that the PML/RAR-alpha fusion protein is expressed in most cases of APL, and this protein presumably contributes to leukaemia initiation and/or progression. PML/RAR-alpha appears to specifically block the further differentiation of myeloid progenitor cells, although the mechanism of its action is not known. It may inhibit the transcription of RAR- or PML-regulated genes, in which case expression must be restored in the presence of therapeutic RA concentrations. However, the possibility remains that PML/RAR-alpha may have a novel function. In order to elucidate the molecular pathogenesis of APL, several important questions remain to be answered. These include whether PML is a transcription factor; the identification of its target genes and response elements, and the role of PML/RAR-alpha and RA in their regulation. Also whether the expression of PML/RAR-alpha in bone marrow cells (either by itself or in combination with other oncogenes) alters their tumourigenicity or differentiation potential. It is also important to determine the function(s) of PLZF and PLZF/RAR-alpha, and determine whether other APL patients with mutations involving PML or RAR-alpha (but not both) respond to therapy with all-trans-RA. Finally, it is important both for the understanding of the molecular biology of APL and its therapy, to determine the effects of other regulatory factors involved in the control of myeloid cell differentiation such as granulocyte colony stimulation factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF) on APL cells in vitro and in vivo, both at presentation and in the RA-resistant patients in relapse.