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Induction of murine leukemia and lymphoma by dominant negative retinoic acid receptor α

✍ Scribed by Y. Alan Wang; Kate Shen; Yasumasa Ishida; Yaolin Wang; Akira Kakizuka; S.C. Brooks

Publisher
John Wiley and Sons
Year
2005
Tongue
English
Weight
351 KB
Volume
44
Category
Article
ISSN
0899-1987

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✦ Synopsis

Acute promyelocytic leukemia (APL) is invariably associated with chromosomal translocation to retinoic acid receptor a (RARa) locus. In a vast majority of cases, RARa translocates to and fuses with the promyelocytic leukemia (PML) gene. It was thought that the fusion protein PML-RARa acts as a double dominant negative mutant to inhibit the PML and RARa 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 RARa 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 RARa 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 RARa signaling was the first essential step in the development of APL in vivo.

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