Mechanisms of regulation in acute promyelocytic leukemia

Expression of the fusion protein PML/RARa is an event pathogenetically linked to the development of APL. Biochemically, the fusion protein has been demonstrated to be part of nuclear HMW complexes (Nervi et al, 1992). We provide evidence that such complexes are composed of PML/RARa oligomers and exist in vivo: the coiled coil region of PML is a critical determinant for their assembly and is responsible for abnormal recruitment of NCoR-HDAC complexes, transcriptional repression, and impaired differentiation of primary hematopoietic precursors. Fusion of RARa to an heterologous oligomerization domain recapitulated the properties of PML/RARa, indicating that oligomerization per se is sufficient to achieve transforming potential. We extend these observations to other AML fusion proteins (PLZF/RARa, NPM/RARa, and AML1/ETO), suggesting that oligomerization of a transcription factor may represent a frequent mechanism of oncogenic conversion. In another aspect of this work, analysis of the subnuclear distribution and nuclear matrix association of PML/RARa and other AML fusion proteins suggests that they all show a subnuclear distribution different from that of their physiological counterparts, suggesting that the delocalization may play a role in the leukemogenetic process. We identified a region in PML, lost in the fusion protein, that promotes the nuclear matrix targeting of PML and correct assembly of nuclear matrix associated PML domains, via a modulation of the oligomerization state of the protein. PML/RARa acts negatively on the oligomerization state of PML, and this effect requires oligomerization and proper targeting of RARa to PML-associated nuclear domains. We suggest that the altered regulation of oligomerization state of both PML and RARa is likely to represent an unifying biochemical mechanism impinging on the complex process of the pathogenesis of APL