Induction of murine leukemia and lymphoma by dominant negative retinoic acid receptor alpha.
Acute promyelocytic leukemia (APL) is invariably associated with chromosomal translocation to retinoic acid receptor alpha (RARalpha) locus. In a vast majority of cases, RARalpha translocates to and fuses with the promyelocytic leukemia (PML) gene. It was thought that the fusion protein PML-RARalpha acts as a double dominant negative mutant to inhibit the PML and RARalpha signaling. In an attempt to study the physiological role of retinoic acid in mammary gland development, we created a transgenic model system expressing a dominant negative RARalpha under the regulation of murine mammary tumor viral promoter. We found that the transgene was also targeted to the lymphoid system in addition to mammary gland. Here we showed that dominant negative RARalpha induced acute lymphoblastic leukemia and lymphoma development in the transgenic mice. Retinoic acid blocked tumor development ex vivo through induction of apoptosis. Thus, our results suggested that disruption of RARalpha signaling was the first essential step in the development of APL in vivo.
Wang
Y Alan
YA
Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Shen
Kate
K
Ishida
Yasumasa
Y
Wang
Yaolin
Y
Kakizuka
Akira
A
Brooks
S C
SC
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015996:Survival Rate; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin