The Bcr-Abl kinase, produced by a chromosomal translocation known as the Philadelphia chromosome, induces CML by driving aberrant differentiation of hematopoietic stem cells. Relevant to this proposal, Bcr-Abl is thought to promote CML by causing elevated expression of the oncoprotein, c-Myc. CML patients in the early stages of the disease, known as chronic phase (CP) are usually responsive to tyrosine kinase inhibitors (TKIs) that target Bcr-Abl, in that the 5 year progression-free survival rate is 89%. However, long-term remission is rarely achieved and patients usually experience relapse upon cessation of TKI treatment. This has been interpreted as indicating that a population of leukemia initiating cells (LICs) is refractory to TKI treatment. LICs are thought to possess properties similar to hematopoietic stem cells such as self-renewal and quiescence, rendering them resistant to therapy, including TKI treatment. Indeed transplantation studies in mouse CML models have suggested that only this small population can initiate disease in new animals. Taken together, these findings suggest that CML LICs serve as a reservoir of BCR-ABL possessing but TKI-resistant cells that prevent remission. CML patients diagnosed with more advanced disease usually do not experience long-term survival, but instead, after initially responding to TKIs, relapse with resistant disease, usually resulting from kinase domain mutations of Bcr-Abl. This is likely the result of a larger pool of LICs in such patients. Clearly, new approaches are needed to effectively treat both chronic and acute phases of CML. It has been shown that deletion of FBW7, which encodes the substrate binding subunit, the SCFFbw7 ubiquitin ligase, in mouse CML models drives LICs out of quiescence and promotes their apoptosis, as well as sensitizing them to TKIs. These effects have been shown to be the result of stabilization and resultant elevated levels of c-Myc, which is already expressed at high levels in LICs. Therefore, we are proposing to use mouse CML models to determine whether SCFFbw7 small molecule inhibitors have therapeutic potential in CML.
Chronic myelogenous leukemia (CML) is a common malignancy that usually responds to therapy that targets the Bcr-Abl tyrosine kinase. However long-term remission is usually not attained because stem-like leukemia initiating cells are resistant to this treatment. This proposal seeks to test a novel small molecule that is likely to target specifically the leukemia initiating cell population of CML thereby enhancing the efficacy of Bcr-Abl inhibitors in achieving long-term remission.
