CONSTITUTIVE ACTIVATION OF JAKS AND STATS IN BCR-ABL-EXPRESSING CELL-LINES AND PERIPHERAL-BLOOD CELLS DERIVED FROM LEUKEMIC PATIENTS

An important step in the oncogenic transformation of hemopoietic cells and the subsequent development of leukemia is the proliferation of tu mor cells in the absence of exogenous growth factors, In most cases of chronic myelocytic leukemia and in some cases of acute myelocytic leu kemia and acute lymphocytic leukemia, the bcr-abl oncogene is involved in this process, Although the BCR-Abl oncoprotein demonstrates enhanc ed tyrosine kinase activity in leukemic cells, the mechanism by which this leads to growth factor independence remains poorly defined, One p roposed mechanism is the activation of cytokine signal transduction pa thways, possibly by an autocrine loop involving IL-3 and/or granulocyt e-macrophage CSF, Examination of several different cell lines expressi ng BCR-Abl demonstrates that some of these cells have constitutive act ivation of the JAK/STAT signaling pathway, We have found the constitut ive activation of STAT5 in most, but not all, cell lines expressing BC R-Abl, This constitutive activation of STAT5 is variably associated wi th a corresponding activation of JAK kinases, Ab blocking studies show that the activation of STAT5 in these cell lines cannot be attributed to the activation of an IL-3/granulocyte-macrophage CSF-driven autocr ine loop, Interestingly, samples of peripheral blood cells derived fro m patients with acute myelocytic leukemia and chronic myelocytic leuke mia, which express BCR-Abl, demonstrate constitutive activation of STA T family members, These studies suggest that in a variety of leukemic states, BCR-Abl may use a bypass mechanism to activate cytokine signal transduction pathways.