Zeev Estrov, M.D.
University of Texas M.D. Anderson Cancer Center
Abstract:
In chronic lymphocytic leukemia (CLL), some of the leukemic cells proliferate whereas others are long-lived and accumulate. CLL cells from different patients differ in that they may have aberrations in certain genes named V genes, and they may express either high or low levels of proteins called CD38 and Zap70. However, despite this patient-to-patient heterogeneity, a protein, called STAT-3, is activated in almost all CLL patients.
Hormone-like substances, termed cytokines and growth factors, circulate in the blood, attached to cells, and induce cellular multiplication. They accomplish this by activating a pathway that exists in cells, called JAK-STAT. When cytokines or growth factors attach to a cell, the JAK component of this pathway is stimulated, and JAK proteins activate STAT proteins. Activated STATs move to the cell’s nucleus and induce the cells to proliferate and to better protect themselves from insults that might cause cell death. We found that in 31 of 32 patients with CLL, one of the STAT proteins, STAT-3, is activated in an unusual manner. The phosphate that induces STAT-3 activation is attached to a serine rather than a tyrosine (as usually found in other leukemias). Nevertheless, our preliminary data suggest that serine-phosphorylated STAT-3 is biologically active in CLL.
In the proposed study we intend to: 1) Find out what causes STAT-3 to be serine-phosphorylated and activated in CLL; 2) Determine whether serine phosphorylation of STAT-3 induces the proliferation of CLL cells and whether it improves the capability of CLL cells to protect themselves from insults that might cause cell death; and 3) Identify drugs that inhibit the activity of STAT-3 and have the potential to be used in therapies for CLL.