Characterisation of the PML/RAR alpha rearrangement associated with t(15;17) acute promyelocytic leukaemia.

The vast majority of cases of APL are associated with t(15; 17) leading to the formation of PML-RAR alpha, RAR alpha-PML and aberrant PML fusion products. PML-RAR alpha is invariably transcribed and is believed to mediate leukaemogenesis. PML was initially considered to be a transcription factor. However, characterisation of other RING finger containing proteins shows no direct evidence for DNA binding. The RING, B-box, and coiled-coil domains are more likely to represent sites of protein-protein interaction and may be critical for the stability of the multiprotein nuclear domains of which PML is an integral part. In APL the nuclear bodies become disrupted, presumably as a consequence of the presence of PML-RAR alpha and aberrant PML proteins that might render the structure unstable. PML-RAR alpha is capable of binding RXR and sequestering it into the disrupted nuclear domains. Sequestration of RXR would be expected to limit high affinity binding of VDR, TR and residual RARs to DNA response elements and might account for the block in myeloid differentiation at the promyelocyte stage that characterizes APL. Recently PML has been found to have growth suppressor/anti-oncogenic activity. It is unclear whether this is a property of PML itself or reflects a nonspecific function of the PML-associated nuclear domains. Hence the PML/RAR alpha rearrangement alone may be sufficient to cause APL. Abnormal PML function may prevent its growth-suppressor activity, leading to leukaemic transformation; concomitant disruption of retinoid pathways due to sequestration of RXR and/or an abnormal repertoire and character of response element activation mediated by the fusion protein, causing the block in myeloid differentiation (Fig. 3). Disruption of RAR alpha would be expected to account for the similar leukaemic phenotype associated with the t(5;17) and t(11;17) APL cytogenetic variants. Further characterisation of NPM and PLZF at the structural and functional level will determine whether PML and other proteins disrupted in APL associated translocations play an active or purely permissive role in leukaemogenesis and will help dissect the events leading to transformation from those causing blockade of myeloid differentiation and mediating the response to ATRA.