The nonrandom chromosomal translocation t(15;17)(q22;q21) in acute pro
myelocytic leukemia (APL) juxtaposes the genes for retinoic acid recep
tor alpha (RAR alpha) and the putative zinc finger transcription facto
r PML. The breakpoint site encodes fusion protein PML-RAR alpha, which
is able to form a heterodimer with PML. It was hypothesized that PML-
RAR alpha is a dominant negative inhibitor of PML. Inactivation of PML
function in APL may play a critical role in APL pathogenesis. Our res
ults demonstrated that PML, but not PML-RAR alpha is a growth suppress
or. This is supported by the following findings: (i) PML suppressed an
chorage-independent growth of APL-derived NB4 cells on soft agar and t
umorigenicity in nude mice, (ii) PML suppressed the oncogenic transfor
mation of rat embryo fibroblasts by cooperative oncogenes, and (iii) P
ML suppressed transformation of NIH 3T3 cells by the activated neu onc
ogene. Cotransfection of PML with PML-RAR alpha resulted in a signific
ant reduction in PML's transformation suppressor function in vivo, ind
icating that the fusion protein can be a dominant negative inhibitor o
f PML function in APL cells. This observation was further supported by
the finding that cotransfection of PML and PML-RAR alpha resulted in
altered normal cellular localization of PML. Our results also demonstr
ated that PML, but not PML-RAR alpha, is a promoter-specific transcrip
tion suppressor. Therefore, we hypothesized that disruption of the PML
gene, a growth or transformation suppressor, by the t(15;17) transloc
ation in APL is one of the critical events in leukemogenesis.