Understanding critical transitions in chronic myeloid leukemia to improve tyrosine kinase inhibitor therapy

PROJECT SUMMARY/ABSTRACT Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm diagnosed in about 5,000 Americans each year, characterized by the presence of the t(9;22) Philadelphia chromosome and its protein product, the BCR-ABL1 tyrosine kinase, in the leukemic cells. Current therapy for CML is centered on tyrosine kinase inhibitors (TKIs) such as imatinib mesylate, which can induce cytogenetic and molecular remissions in most patients, who then enjoy normal age-adjusted life expectancy but usually require lifelong therapy. Despite this clinical success, there are several unmet needs in CML research. One is to identify strategies to increase the rate and depth of response to TKI therapy during the critical first year after diagnosis, when patients are most vulnerable to disease progression. A related need is a better understanding of the mechanisms underlying primary resistance to TKIs, to prospectively identify the ~10-15% of patients who will fail TKI therapy, and for ways to overcome this resistance. Finally, there is a need to understand why some patients can stop TKI therapy without relapsing despite the continued presence of low levels of malignant cells, and to develop rational interventions to help more patients achieve so-called treatment-free remission, which is a surrogate for cure. This Project seeks to address these unmet needs by continuing the application of systems biology approaches to CML under the auspices of the UCI Center for Cancer Systems Biology (CaSB@UCI). In this effort, a mathematical model of normal and CML myelopoiesis that incorporates feedback and feed-forward interactions and recapitulates known features of CML biology and TKI response will be leveraged, in parallel with a novel conditional transgenic bone marrow chimeric mouse model that accurately recapitulates early events in the development of CML. In the first Aim, the cellular and molecular mechanisms of the non-mutational stochastic process underlying a critical transition in CML development will be investigated by increasing the complexity of the mathematical model based on experimental data to gain biological insight into mechanisms of this “tipping point” in leukemogenesis. In parallel, studies in the mouse model (single cell transcriptomics, genome-wide CRISPR screen, and spatial phenotypic analysis) will identify candidate molecules governing this transition, which will then be tested directly using genetic approaches in mice in the second Aim. The third Aim will test interventions in mice that are predicted to enhance TKI effectiveness, including targeting leukemic stem cell proliferation and self-renewal, with the goal of translating these discoveries towards clinical application. The in silico and in vivo approaches will be complementary, with predictions of the quantitative model tested in mice, and results from mice informing the refinement of the mathematical model. The Project will also benefit from interactions with the two other Projects in this P01 application, who seek to understand “tipping points” in solid tumors through similar approaches and technologies. Results from this Project will yield important new knowledge about the pathophysiology of CML and motivate new strategies to improve the therapy of this disease.