Dendritic cells (DC) are bone marrow-derived professional antigen presenting cells (APC) which play the central role in initiating and controlling the primary immune response, via cognate interactions with T and B cells. Clinically, the potent immuno-stimulatory capacity of DC has translated into significant promise as """"""""cellular vaccines"""""""" against solid and hematologic malignancies. One such approach is to differentiate leukemic blasts into DC, and use these DC to induce autologous anti-tumor CTL activity. In normal human hematopoiesis, dendritic cells are a heterogeneous population that arises from distinct hematopoietic progenitor cells (BPC) along distinct differentiation pathways. Different extra-cellular cytokines and intra-cellular signals trigger DC differentiation in vitro. Relatively little is known about the response of leukemias to such DC differentiation signals. Even less is known about the intracellular mechanisms triggered by these signals in normal or leukemic cells. The hypothesis of this application is that undifferentiated and myeloid leukemia cells retain the ability to differentiate into immuno-stimulatory dendritic cells in response to specific signals. Additionally, leukemic cells arrested at differing stages of myeloid differentiation will have different signal requirements necessary to trigger DC differentiation. And for each stage of myeloid differentiation, the specific intracellular signaling pathways that integrate the extra-cellular stimuli will regulate distinct components of DC differentiation and function. The overall goals of this application are twofold: 1). To define and characterize mechanisms that induce leukemic cells to undergo DC differentiate for potential use in immunotherapy as cellular vaccines"""""""" and 2). To gain a broader understanding of the intracellular signaling and genetic events that underlie normal DC differentiation and function.
The specific aims and approach of this application are to: 1). Establish the characteristics of leukemias that can be triggered to differentiate into dendritic cells, and what signals are required, 2). Determine which intracellular signaling pathways integrate the extra-cellular/receptor-mediated stimuli that initiate dendritic cell differentiation, and what component(s) of differentiation/function are regulated by which pathways, 3). Characterize the molecular components of these intracellular signaling pathways, and 4). Identify the nuclear/genetic events regulated by DC differentiation-specific signaling pathways, and their function.
