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.