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

"This study gets at the exact biochemical and genetic cause of the uncontrolled cell growth in this leukemia," says Mitchell A. Lazar, MD, PhD, chief of the division of endocrinology, diabetes, and metabolism. "Understanding the molecular basis of this disease will teach us important lessons about cancer in general." Penn researchers and colleagues from the European Institute of Oncology in Milan report their findings in the February 19 issue of Nature.

The genetic mistake that makes APL so deadly is a translocation between two chromosomes. These chromosomes break and fuse together again during cellular division, resulting in a new gene with material from each. The protein encoded by the new gene is called a fusion protein. Chromosomal translocations figure in many types of cancers.

In 95 percent of APL cases, the fusion protein is a product of a gene called PML on chromosome 15 and the gene for the retinoic acid receptor (RAR) on chromosome 17. In another 4 percent of the cases, the protein is a fusion between the RAR and a gene for a protein of unknown function called PLZF.

"The involvement of the retinoic acid receptor in both forms of APL is key to understanding the complex genetics of this disease," says Lazar. The receptor is regulated by vitamin A, which is converted to the gene-controlling hormone retinoic acid once in the body. "Interestingly, a few years ago, researchers discovered that a Chinese herbal remedy was curing most of the APL cases in which it was used," 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.