Acute Myeloid Leukemia (AML), a heterogeneous group of malignancies of the hematopoietic system, is the most common acute leukemia in adults, with an incidence that is expected to increase as the population ages. Although patients often achieve remission after initial treatment with chemotherapy, relapse remains a significant problem, and the majority of patients eventually succumb to their disease. Several significant aspects of the genesis and progression of AML are related to its interaction with the bone marrow microenvironment: the immune system develops a tolerance for the leukemic cells, and patients lose hematopoietic function over time. As the diagnoses of both the initial leukemia and relapse are made through cytopenias, a better understanding of the events culminating in the development of leukemia both initially and in relapse could potentially allow for earlier detection of disease and new approaches to therapy. Exosomes, small membrane-bound vesicles secreted by many cell types, have recently been demonstrated to carry RNA and protein from cell to cell. This process has recently been shown to occur between AML and cells in its microenvironment, and to contribute to disease progression in other malignancies. Of particular interest is the transfer of certain microRNA shown to regulate both dendritic cell (DC) development and function as well as hematopoietic development and niche adhesion. The work proposed here seeks to delineate the contribution of exosomal communication between AML and its environment to the development of immune tolerance and the erosion of hematopoiesis, two key events in leukemogenesis. In order to achieve this goal, it focuses on exosomal microRNA transfer. It will evaluate the effect this process has on the ability of hematopoietic stem cells to home to and engraft and differentiate in the bone marrow, using in vitro exposure of precursors to exosomes isolated under conditions designed to mimic those encountered in the marrow environment, as well as in vivo modeling using immune-deficient mice. It will further examine the ability of AML-exosomes to suppress the capacity of dendritic cells to develop and initiate an immune response, by evaluating differentiation of mononuclear cells to DC, maturation of DC in response to antigen, and the induction of DC apoptosis in response to exosome exposure.
Communication between acute myeloid leukemia cells and nearby nonmalignant cells in the bone marrow enables the disease to take root, evade destruction by the immune system, and may be an essential mediator in the evolution of the disease. The proposed studies will investigate a recently discovered cell-cell regulatory mechanism , and will contribute to the understanding of the development and progression of this disease.
|Viola, Shelton; Traer, Elie; Huan, Jianya et al. (2016) Alterations in acute myeloid leukaemia bone marrow stromal cell exosome content coincide with gains in tyrosine kinase inhibitor resistance. Br J Haematol 172:983-6|
|Huan, J; Hornick, N I; Goloviznina, N A et al. (2015) Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes. Leukemia 29:2285-95|
|Hornick, Noah I; Huan, Jianya; Doron, Ben et al. (2015) Serum Exosome MicroRNA as a Minimally-Invasive Early Biomarker of AML. Sci Rep 5:11295|
|Conti, Brian J; Devaraneni, Prasanna K; Yang, Zhongying et al. (2015) Cotranslational stabilization of Sec62/63 within the ER Sec61 translocon is controlled by distinct substrate-driven translocation events. Mol Cell 58:269-83|