| This thesis characterizes how elements of the bone marrow microenvironment protect and thereby interfere with treatment of hematological malignancy. The central hypothesis of this work is that osteoblasts, a prominent feature of the bone marrow microenvironment, have the ability to protect acute myeloid leukemia (AML) cells from apoptosis-inducing agents, and do so via a mechanism that depends on their differentiation state. In Chapter 1 (the introduction), AML, SDF-1 and CXCR4, the protective bone marrow microenvironment, and osteoblast differentiation are reviewed. In Chapters 2 and 3, published and soon-to-be-published research results that test the central hypothesis are presented. Chapter 2 includes data and results indicating that differentiating osteoblasts mediate protection of AML cells from cytarabine, and shows results delineating the capacity of histone deacetylase inhibitors to reduce this protection. Chapter 3 shows data and results indicating that tissue non-specific alkaline phosphatase (TNAP) expressed by osteoblasts protects AML cells from apoptosis in response to SDF-1, a chemokine abundant in the bone marrow microenvironment. In Chapter 4 (the discussion), the research results in Chapters 2 and 3 are further discussed within the framework of the field, potential future directions are outlined, and clinical implications are considered. Altogether, this thesis significantly advances knowledge about the cells and molecular mechanisms of the bone marrow microenvironment that protect and interfere with treatment of AML. |
