Role of promyelocytic leukemia (PML) protein in tumor suppression

The promyelocytic leukemia (PML) gene encodes a putative tumor suppressor g ene involved in the control of apoptosis, which is fused to the retinoic ac id receptor alpha (RAR alpha) gene in the vast majority of acute promyelocy tic leukemia (APL) patients as a consequence of chromosomal translocations. The PMLRAR alpha oncoprotein is thought to antagonize the function of PML through its ability to heterodimerize with and delocalize PML from the nucl ear body. In APL, this may be facilitated by the reduction to heterozygosit y of the normal PML allele. To determine whether PML acts as a tumor suppre ssor in vivo and what the consequences of deregulated programmed cell death in leukemia and epithelial cancer pathogenesis are, we crossed PML-/- mice with human cathepsin G (hCG)-PMLRAR alpha or mammary tumor virus (MMTV)/ne u transgenic mice (TM), models of leukemia and breast cancer, respectively. The progressive reduction of the dose of PML resulted in a dramatic increa se in the incidence of leukemia, and in an acceleration of leukemia onset i n PMLRAR alpha TM. By contrast, PML inactivation did not affect neu-induced tumorigenesis. In hemopoietic cells from PMLRAR alpha TM, PML inactivation resulted in impaired response to differentiating agents such as RA and vit amin Dg as well as in a marked survival advantage upon proapoptotic stimuli . These results demonstrate that: (a) PML acts in vivo as a tumor suppresso r by rendering the cells resistant to proapoptotic and differentiating stim uli; (b) PML haploinsufficiency and the functional impairment of PML by PML RAR alpha are critical events in APL pathogenesis; and (c) aberrant control of programmed cell death plays a differential role in solid tumor and leuk emia pathogenesis.