Chronic myelogenous leukemia (CML) occurs predominantly in the elderly with a medium age at diagnosis around 60 years. CML is caused by the oncogenic tyrosine kinase fusion gene BCR-ABL that transforms a normal hematopoietic stem cell (HSC) into a leukemic stem cell (LSC). Several decades of CML research has led to development of the tyrosine kinase inhibitor imatinib as the first successful targeted therapy of human cancer. Despite the great success of imatinib in CML treatment, the drug fails to eradicate LSCs and the disease relapses when the drug is ceased. However, the mechanisms of CML LSC drug resistance are not well understood, which would hamper our effort in finding a cure. Mouse models of CML played a pivotal role for illustrating roles of BCR-ABL in molecular pathogenesis of CML and for studying CML disease progression and therapeutic interventions. However, mouse models are generated in very young mice (2 to 3 months), and it is unknown how advanced age may influence CML in the mouse models and whether CML in older mice may provide an advantage for modeling the human disease in response to the treatment and LSC drug resistance. The goal of this application is to determine whether or not advanced age is an important influencing factor on leukemia progression and pathology, response to drug treatment, as well as LSC drug resistance. Our central hypothesis is that advanced age impacts the experimental outcomes of a mouse model of chronic myeloid leukemia that, in human, has aging as a major risk factor. We will test this hypothesis with a well characterized and widely used mouse model of CML by BCR-ABL transduction of BALB/c mouse bone marrow cells followed by transplantation to lethally irradiated BALB/c recipients. We have recently identified that CML LSCs in this mouse model reside exclusively in CD150- side population. We have discovered that protein lysine deacetylase SIRT1 is activated by BCR-ABL transformation in HSCs and SIRT1 knockout inhibits CML development and depletes CML LSCs in the BALB/c mouse CML model. We have shown that SIRT1 inhibition sensitizes CML cells, particularly LSCs, to imatinib and may help eradicate LSCs. In UH2 phase of this proposal, we will breed sufficient BALB/c mice and SIRT1 knockout mice for the feasibility and UH3 phase studies. In UH3 phase, we will continue the maintenance of aging mice and produce additional mice for aging and control. We will study three specific aims: 1) To determine the age impact on CML disease progression and LSCs. 2) To determine age impact on CML LSCs in response to tyrosine kinase inhibitor treatment. 3) To determine the impact of age on SIRT1 inhibition for eradicating CML LSCs. Successful completion of the proposed studies will shed new insight into the effect of age on CML LSC drug resistance and may lay a foundation for the use of aged mice for CML research for improved outcomes.
This proposal addresses how advanced age may affect the experimental outcomes (leukemia progression, pathology and response to drug treatment) of a mouse model of human chronic myeloid leukemia that has aging as a major risk factor. The proposed studies are important and have direct relevance to human health because current mouse models of chronic myeloid leukemia only use very young mice for the studies and may miss certain key aging effectors. Successful completion of the proposed studies will shed new light on the effect of age on modeling human chronic myeloid leukemia and drug resistance of leukemic stem cells and may lay a foundation for future discoveries of new therapeutic interventions with improved mouse models.
