Defining the role of beta2-integrin signaling for regulating cell survival, proliferation and apoptosis in acute myeloid leukemia

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Acute myeloid leukemia (AML) cells receive oncogenic signals from the bone marrow microenvironment. These signals trigger AML cell proliferation and protect AML cells from therapeutic interventions, but the molecular basis of this phenomenon is yet poorly understood. By investigating the molecular nature of spleen tyrosine kinase (Syk) function in AML cells in vitro, we discovered that beta2-integrins including Mac-1 are involved in oncogenic signaling by activating Syk and the transcription factors STAT3 and STAT5 in the context of AML cell/bone marrow stroma interactions. Beta2-integrins are leukocyte-restricted adhesion receptors that anchor cells to the extracellular matrix (ECM) or adjacent cells. The transmembrane receptors are widely expressed in the myeloid lineage as well as proliferating hematopoietic stem cells. Moreover, Mac-1 expression in AML cells correlates with a poor prognosis, albeit the underlying molecular mechanism is not understood to date. Apart from mediating cellular adhesion, beta2-integrins are known to regulate complex signaling networks in immune cells and thereby control diverse cellular functions including proliferation and differentiation. The mechanisms involved in beta2-integrin signal transduction are complex as they implicate cytoskeletal changes, GTPase-, phosphoinositide- and tyrosine kinase signaling. Hence, our hypothesis is that beta2-integrins including Mac-1 might function as promoters of AML cell growth and survival also in vivo by activating oncogenic signaling cascades upon their engagement in the bone marrow niche. The object of the present research proposal is to further characterize the role of beta2-integrins in the onset and progression phases of AML. To address this aim, we propose 1.) to define the in vivo role of beta2-integrins in AML using murine retroviral transplantation models, 2.) to uncover the beta2-integrin/Mac-1-dependent signaling networks in AML cells by (phospho)proteomic techniques and 3.) to characterize the stroma-mediated effects on AML cell behavior. By the proposed experimental approach, we will elucidate the molecular properties of integrin signaling and their impact on AML cells in the presence of a protective bone marrow microenvironment. A better understanding of the oncogenic effects mediated through intercellular interactions is needed for the further improvement of cytotoxic and targeted AML therapies.