Leukemia Linked to Excess Enzyme Isoform Activity

Cancer researchers have identified an enzyme that plays a critical role in the development of the common adult form of blood cancer, chronic lymphocytic leukemia (CLL).

Investigators at the University of California, San Diego (La Jolla, CA, USA compared enzyme activities in white blood cells from patients with CLL to those of healthy adults. In particular, they were interested in isoforms of a group of enzymes known as cyclic nucleotide phosphodiesterases.

They reported in the November 26, 2008, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) that the level of phosphodiesterase 7B (PDE7B), which regulates cellular levels of cyclic AMP, was 10 times higher in CLL patients than in normal individuals. Cyclic AMP is required to drive apoptosis, a process that is defective in CLL cells. The investigators found that treating CLL cells with an inhibitor of PDE7B raised the level of cyclic AMP and selectively increased apoptosis.

"PDE7B is thus a new drug target for CLL,” said senior author Dr. Paul Insel, professor of pharmacology and medicine at the University of California, San Diego. "We have preliminary data from patient samples studied in the laboratory showing that we can increase the killing of CLL cells even more if we block PDE7B and also add other drugs used to treat CLL. We think that CLL cells may have found ways to help keep themselves alive by preventing cAMP from increasing. This paper provides a validation of the importance of the cAMP pathway as a target for drugs that might be used to treat CLL.”

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