The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease

Acute promyelocytic leukaemia (APL) is one of the more common subtypes of acute myeloid leukaemia (AML), accounting for 10±15% of de novo cases in younger adults (Stone & Mayer, 1990; Avvisati et al, 1992). The disease is characterized by a number of features which emphasize the need for accurate diagnosis and demand a highly speci®c treatment approach. These include a potentially devastating coagulopathy that can lead to rapid demise particularly due to cerebral haemorrhage; sensitivity to anthracyclinecontaining chemotherapy regimens which are associated with a relatively low relapse risk, such that bone marrow transplantation in ®rst remission has been found to confer no overall bene®t; and a dramatic differentiation response to retinoids such as all-trans retinoic acid (ATRA) which have transformed clinical practice for this condition in recent years (Avvisati et al, 1992; Fenaux et al, 1997b; Burnett et al, 1998). Early studies showed that treatment with ATRA could achieve remission rates comparable to conventional chemotherapy in newly diagnosed APL, but in addition demonstrated bene®t in a series of patients previously resistant to chemotherapy or treated in relapse (Huang et al, 1988; Castaigne et al, 1990; Chomienne et al, 1990). Subsequent studies have demonstrated that combining ATRA with chemotherapy signi®cantly improves outcome than when either modality is used alone (Kanamaru et al, 1995; Fenaux et al, 1997b; Tallman et al, 1997; Burnett et al, 1999). A further exciting development relates to recent reports detailing impressive responses to arsenic-based compounds (Shen et al, 1997; Soignet et al, 1998), although the optimal place of these agents in the management plan remains to be determined. Since the late 1970s it has been appreciated that APL is correlated with the reciprocal translocation, t(15;17) (q22;q21), present in the majority of cases (Rowley et al, 1977; Larson et al, 1984). However, it was not until 1990 that the APL breakpoint region was ultimately cloned, and the signi®cance of the response to retinoids noted in early clinical studies became apparent (Borrow et al, 1990; de TheÂ et al, 1990). The translocation was found to disrupt a previously uncharacterized gene, PML on chromosome 15, and the retinoic acid receptor-a gene (RARa) on 17 (de TheÂ et al, 1990, 1991; Alcalay et al, 1991; Goddard et al, 1991; Kakizuka et al, 1991). RARa belongs to the steroid hormone receptor superfamily and acts as a transcription factor mediating the effect of retinoic acid (RA) at speci®c response elements (see Chambon, 1996, and references therein). The realization that the resultant PML-RARa fusion protein retains the RA ligand binding domain suggested that it may not only mediate leukaemogenesis but also account for the unique sensitivity of APL to differentiation by retinoids such as 9-cis RA and ATRA. Over the last few years three further reciprocal translocations associated with APL have been identi®ed (Chen, S.-J., et al, 1993; Chen, Z., et al, 1993; Redner et al, 1996; Wells et al, 1997). In each case 17q21 was involved leading to disruption of RARa, which was fused to a gene other than PML. It is now apparent that the nature of the fusion partner has a signi®cant bearing on ATRA responsiveness, and hence the optimal treatment approach for these disease entities. Over the last decade research has been aimed at determining the role of retinoid receptors in haemopoietic differentiation, how chimaeric retinoid receptors resulting from the t(15;17) and alternative translocations might promote leukaemogenesis, the normal function of PML, the mechanisms by which ATRA and arsenic reverse the leukaemic phenotype, and ®nally evaluating the role of molecular analyses as a means of directing treatment in patients with this condition. This work has ®rmly established APL as the ®rst disease in which successful therapeutic approaches have been developed that directly address and overcome the underlying molecular lesion.