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Hormone Control Of Rare Leukemia Sheds Light On Molecular Basis Of Cancer

" he notes. "It turns out that the active ingredient was retinoic acid derived from vitamin A. The overwhelming majority of APL patients treated with retinoic acid go into remission, but a small portion of patients do not."

Retinoic acid and its receptor regulate gene expression using a complex interplay of blocking and activating molecules. In the absence of retinoic acid, the receptor blocks a gene by binding to a co-repressor. In the presence of the hormone, the co-repressor is released and a co-activator turns a gene on. The retinoic acid receptor part of both the PML and PLZF fusion proteins binds the co-repressor.

"Our work shows that in 95 percent of APL cases, retinoic acid essentially kicks off the co-repressor, allowing genes to get turned on, and the leukocytes are allowed to progress along their correct path of development, not reproduce uncontrollably," explains Lazar. "This demonstrates why retinoic acid works as a treatment in the vast majority of APL cases--the ones involving the PML fusion protein."

In a small percent of the cases--the ones involving PLZF--retinoic acid doesn't release the co-repressor. "Unfortunately, the PLZF part of the fusion protein binds the co-repressor in such a way that's not regulated by retinoic acid," says Lazar. "There have been many theories to explain the molecular biology of this leukemia, but this is the first to explain why retinoic acid is a wonderful treatment for some, but not all, cases. As far as treatment is concerned, the next step is to directly target the co-repressors."

Italian researchers Saverio Minucci and Pier Giuseppe Pelicci collaborated on this study, which was funded in part by the National Institute for Diabetes, Digestive, and Kidney Diseases.

Editor's Note: Dr. Lazar can be reached at 215-898-0210 The University of Pennsylvania Medical Center's sponsored rese
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Contact: Karen Young Kreeger
kreeger@mail.med.upenn.edu
215-662-2560
University of Pennsylvania School of Medicine
18-Feb-1998


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