This Program Project Grant focuses on development of novel, effective therapies for CML, based upon its molecular pathophysiology and its unique susceptibility to biologic therapies, allotransplantation and immunotherapeutic approaches. This program has been highly productive, with continuous funding for the last 19 years. The program is reorganized with 2 new projects in the competitive renewal to address the major issues and therapeutic opportunities in this field. This is a highly integrated program of 6 projects and 5 cores are proposed forming a comprehensive translational research program with investigation spanning the basic biology of CML to human clinical trials. This amended application is extensively revised to address the critique of the review. Project 3 from the A1 application is deleted and the projects are renumbered. Projects 1 and 2 involve clinical investigations translating scientific advances from the projects into human clinical trials designed to increase the rate of molecular complete remission and disease free survival in CML. Project 1 studies chemo-biologic therapies assessing tyrosine kinase inhibitors, antigen specific immunotherapy and hypomethylating therapy designed to overcome imatinib resistance. Project 2 involves novel strategies for hematopoietic transplantation focusing on enhancement of graft-vs-leukemia and antigen specific cellular immunotherapy against PR1, post transplant hypomethylating therapy and chemosensitization by interference with interaction of SDF-1 and CXCR4 to improve the therapeutic index. . Project 3 examines the interaction ofthe microenvironment and CML, and potential therapeutic interventions to interfere with these interactions. Project 4 evaluates the mechanisms of resistance to tyrosine kinase inhibitors in CML stem cells and potential therapeutic interventions to circumvent resistance. Project 5 examines molecular mechanisms of bcr-abl oncogenesis secreted cell death factors, lipocalins, and signaling through Jak-2. Project 6 examines the epigenome in CML, including Predictive and prognostic testing of selected epigenetic markers and pharmacodynamic analysis of epigenetic parameters in patients treated with hypomethylating therapies. Five cores are included: Core A is the administrative core. Core B is biostatistics. Core C provides cell culture and clonogenic assays. Core D is the cell collection and distribution core. Core E is the GMP Cell Laboratory and Immune Assessment Core, required for cell processing for human clinical trials and immune assessments required for these studies and the research projects. This is a productive, highly integrated program for development of novel therapies for CML.