Human chronic myelogenous leukemia (CML) is induced by the BCR-ABL oncogene. CML often initiates in a chronic phase and eventually progresses to an advanced terminal blastic phase, in which either acute myeloid or acute lymphoid leukemia develops. Thus, a successful treatment of CML requires dealing with diseases in both chronic and advanced phases. BCR-ABL is an oncogenic kinase. It is generally believed that shutting down the kinase activity of BCR-ABL will completely inhibit its functions, leading to inactivation of its downstream signaling pathways and consequently stopping cellular transformation by BCR-ABL. Therefore, current efforts in chemotherapy for CML largely focus on targeting BCR-ABL using kinase inhibitors.

The BCR-ABL kinase inhibitor Gleevec is the preferred treatment for CML and has been shown to induce a complete hematologic response in almost all chronic phase CML patients. However, Gleevec is unable to completely kill leukemic cells, and patients develop drug resistance. Moreover, Gleevec is much less effective in treating advanced phase CML patients. Our studies in mice show that Gleevec prolongs survival of CML mice, but does not cure the disease. We also have shown that Gleevec is not effective in treating mice with advanced phase CML. The inability of Gleevec to cure CML in mice leads us to believe that the BCR-ABL kinase also activates some signaling molecules that cannot be inhibited by Gleevec and that play a critical role in CML development. These molecules must be identified and targeted to achieve curative therapy of CML.

We have found that a group of proteins called Src kinases are activated by BCR-ABL, but their activation is not inhibited by Gleevec. We have developed a significantly improved mouse model of human CML, allowing us to ask critical questions that would be difficult or impossible to address using studies of cultured cells or primary leukemia cells from patients.

The first aim is to determine the effect of Src kinases in survival and growth of BCR-ABL-expressing leukemic stem cells. This approach will help identify effective targets for killing these stem cells. The second aim is to test whether lack of Src kinases prevents transition of CML chronic phase to advance phase. If this is true, it suggests that anti-Src therapy should start in the chronic phase of CML, which has not been proposed for treating CML patients. The third aim is to determine whether activation of Src kinases by BCR-ABL provides a mechanism for insensitivity of advanced phase CML to Gleevec treatment. This will help explain why advanced phase CML patients do not respond to Gleevec therapy and suggests use of combination therapy (anti-BCR-ABL in combination with anti-Src kinases) in CML patients.

Our proposed study provides a new idea that targeting BCR-ABL kinase alone by Gleevec will not lead to a cure of CML, because some signaling molecules that cannot be inhibited by Gleevec are also essential to the development of CML. These molecules must be inhibited in CML therapy. Our study will provide a new therapeutic strategy for CML.