Drugs May Restore Tumor Suppression Activity in Promyelocytic Leukemia

In order to function correctly as a tumor suppressor, PTEN (phosphatase and tensin homologue) requires a complicated network of protein interactions to maintain a precise location within the cell nucleus.

Investigators from Harvard Medical School (Cambridge, MA, USA) have found that even when PTEN (the most frequently mutated tumor suppressor) is produced normally by a cell, it will fail to function if it is not transported into the cell's nucleus.

The researchers reported in the August 20, 2008, online issue of the journal Nature that translocation of PTEN into the nucleus requires the combined activities of several different proteins. These data were obtained by studying the situation in acute promyelocytic leukemia (APL). Cells of this type of cancer have normal PTEN but an inhibited version of promyelocytic leukemia protein (PML). Normally, PML blocks the activity of a different protein called HAUSP, which removes PTEN from the nucleus. PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein).

In promyelocytic leukemia PML function is disrupted by the PML-RAR-alpha fusion oncoprotein, but treatment with drugs that trigger PML-RAR-alpha degradation, such as all-transretinoic acid or arsenic trioxide, restore nuclear PTEN.

"Our laboratory recently discovered that even when PTEN is produced normally by a cell, it has to be properly localized within the nucleus in order to maintain its full tumor suppressive abilities,” explained senior author Dr. Pier Paolo Pandolfi, professor of medicine at Harvard Medical School. "Indeed, it has been demonstrated that in a variety of cancers, PTEN has broken away from the nucleus. With these new findings, we now understand how this happens. The modulation of the PML-HAUSP pathway offers us an exciting and unique approach to enhancing the tumor suppressive actions of PTEN. Because PML is known to be "druggable,” we believe that in cases of APL, modulation of PTEN function can be achieved with drugs already being used for the treatment of human cancers, including interferon and all transretinoic acid.”

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