Zeev Estrov, M.D. University of Texas MD Anderson Cancer Center

BIOLOGY

Role of STAT3 in CLL Pathobiology

Update:

In chronic lymphocytic leukemia (CLL), some of the leukemic cells proliferate whereas others are long-lived and accumulate. Hormone-like proteins, termed cytokines and growth factors, circulate in the blood, attach to cells' membrane and activate STAT proteins that bind to DNA and enhance protection from insults that cause cell death and cellular multiplication. We studied CLL cells from about 100 patients, and found in all of the patients, that one of the STAT proteins, STAT-3, is activated spontaneously in an unusual manner. The phosphate that induces STAT-3 activation is attached to a different location on the DNA than other malignant disorders.

The unusual spontaneous activation of STAT-3 remains unchanged for days when CLL cells are maintained in culture, and the inhibition of STAT-3 results in CLL cell death. Because Azacytidine, a drug recently approved for treatment of myelodysplastic syndrome, inhibits the activation of STAT-3, we initiated a phase II trial of Azacytidine in CLL. Thus far, 1 of the 7 patients with CLL enrolled onto the study has benefited clinically.

We have been concentrating our efforts on identifying the mechanism(s) that induces spontaneous activation of STAT-3 which, in our view, is crucial for unraveling the molecular event(s) that contribute to the evolution of CLL