Signal transduction in chronic myelogenous leukemia
Apoptosis Regulatory Proteins
Carcinoma, Non-Small-Cell Lung
Drug Resistance, Neoplasm
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein Kinase Inhibitors
The focus of our laboratory is to define the mechanism by which the BCR-ABL tyroslne kinase fusion protein causes chronic myelogeonous leukemia (CML). The adaptor proteins GRB2 and SHC have been linked to the RAS-dependent transformation pathway of the BCR-ABL. We now have evidence Implicating a third adaptor protein, CRKL, In this pathway. CRKL was recently Identified as a substrate for BCR-ABL in patients with CML. Here we report that CRKL Is phosphorylated when overexpressed, activates RAS and JUN Klnase (JNK) signaling pathways, and transforms flbroMasts in a RAS-dependent fashion, analogous to BCR-ABL. We examined the rale of CRKL in BCR-ABL transformation by deleting the CRKL binding site in BCR-ABL. This mutant BCRABL protein has reduced transforming activity in fibrobiasts. These results show that activation of CRKL is sufficient for oncogenesis and directly implicate CRKL in BCR-ABL transformation. Using CML as a model, we have also tested the hypothesis that cytokineindepandent growth of leukemia cells results from aberrant activation of cytokine signaling pathways. The STATS (signal transducer and activator of transcription) protein, which is activated transiently In normal myeloid cells by cytokines such as GM-CSF (granulocyte-macropnage colony stimulating factor), was constitutively activated in cell lines derived from CML patients, even in the absence of GM-CSF STATS was also activated in primary mouse bone marrow cells acutely transformed by the CML-specmc BCR-ABL oncogene, but not by the serine kinase oncogene vMOS. Reconstitution experiments in non-hematopoletlc cells show that STATS activation by BCR-ABL occurs independent of cytokines. Results using BCR-ABL mutants which specifically uncouple connections to known signal transduction pathways show that STATS activation is kinase dependent and correlates directly with ability to confer cytokine independent growth in hematopoietic cells. These findings suggest that STATS plays a role in hematopoietic transformation by BCRABL.