THE ROLE OF STATS IN TRANSFORMATION BY BCR/ABL

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The chimeric fusion protein Bcr/Abl has been implicated in a variety of human hematologic malignancies, including the vast majority of cases of chronic myelogenous leukemia (CML), 20-30 percent of acute lymphocytic leukemia (ALL) in adults, and rare cases of acute myelogenous leukemia (AML). Recently it has been demonstrated that P210BCR/ABL activates members of the signal transducers and activators of transcription (STAT ) family members, implicated in cytokine and growth factor signaling pathways. STAT5 is the major STAT activated by p210BCR/ABL and STAT5 activation is a common feature in Philadelphia chromosome positive (Ph+) cell lines. P190BCR/ABL and v-AB1, which share the propensity for lymphoid transformation in vivo, differ from P210 in that they also STAT6, implicated in IL-4-dependent lymphoid signaling. This proposed work has two broad purposes (1) to determine the role of STAT5 activation in P210 transformation. This will be investigated by introducing dominant negative forms of STAT5 into hematopoietic factor- dependent cell lines and determining whether they interfere with the ability of P210 to render these cells cytokine independent. Also, murine bone marrow cells, co-expressing both P210 and dominant negative STAT5, will be used to reconstitute lethally- irradiated mice to determine whether dominant negative STAT5 impairs P210-induced leukemia in vivo. In a complementary experiment, wild-type mice will be reconstituted with P210- infected bone marrow from STAT5A and STAT5A/5B knockout mice to determine whether recipient animals show resistance to P210- induced leukemia. P210-infected STAT5 knockout bone marrow will also analyzed for defects in hematopoietic transformation in vitro by a myeloid colony assay (2) to determine the role of STAT6 activation in transformation by P190 and v-Abl This will be accomplished by introducing either P 190 or v-Abl into bone marrow cells from mice with homozygous deficiency of STAT6 by retroviral gene transfer, and assessing transformation in Whitlock-Witte and soft agar colony assays in vitro, and for the ability of these cells to induce leukemia in vivo when used to reconstitute lethally-irradiated STAT6 wild-type animals. Insight into the role of STAT activation by Bcr/Abl and v-Abl may lead to novel targeted therapies for patients afflicted with Philadelphia chromosome positive leukemias.