CELL-DEATH INDUCTION BY THE ACUTE PROMYELOCYTIC LEUKEMIA-SPECIFIC PMLRAR-ALPHA FUSION PROTEIN/

PML/RAR alpha is the abnormal protein product generated by the acute p romyelocytic leukemia-specific t(15;17), Expression of PML/RAR alpha i n hematopoietic precursor cell lines induces block of differentiation and promotes survival, We report here that PML/RAR alpha has a potent growth inhibitory effect on all nonhematopoietic cell lines and on the majority of the hematopoietic cell lines tested, Inducible expression of PML/RAR alpha in fibroblasts demonstrated that the basis for the g rowth suppression is induction of cell death, Deletion of relevant pro myelocytic leukemia (PML) and retinoic acid receptor (RAR alpha) domai ns within the fusion protein revealed that its growth inhibitory effec t depends on the integrity of the PML aminoterminal region (RING, B1, B2, and coiled coil regions) and the RAR alpha DNA binding region, Ana lysis of the nuclear localization of the same PML/RAR alpha deletion m utants by immunofluorescence and cell fractionation revealed that the biological activity of the fusion protein correlates with its microspe ckled localization and its association to the nuclear matrix. The PML aminoterminal region, but not the RAR alpha zinc fingers, is required for the proper nuclear localization of PML/RAR alpha, We propose that the matrix-associated microspeckles are the active sites of PML/RAR al pha and that targeting of RAR alpha sequences to this specific nuclear subdomain through PML sequences is crucial to the activity of the fus ion protein on survival regulation.