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Induction of murine leukemia and lymphoma by dominant negative retinoic acid receptor α
Author(s) -
Wang Y. Alan,
Shen Kate,
Ishida Yasumasa,
Wang Yaolin,
Kakizuka Akira,
Brooks S.C.
Publication year - 2005
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20144
Subject(s) - biology , retinoic acid , acute promyelocytic leukemia , cancer research , retinoic acid receptor , leukemia , transgene , promyelocytic leukemia protein , retinoic acid receptor alpha , lymphoma , genetically modified mouse , microbiology and biotechnology , immunology , gene , genetics
Abstract Acute promyelocytic leukemia (APL) is invariably associated with chromosomal translocation to retinoic acid receptor α (RARα) locus. In a vast majority of cases, RARα translocates to and fuses with the promyelocytic leukemia (PML) gene. It was thought that the fusion protein PML‐RARα acts as a double dominant negative mutant to inhibit the PML and RARα 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 RARα 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 RARα 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 RARα signaling was the first essential step in the development of APL in vivo. © 2005 Wiley‐Liss, Inc.