In acute lymphoblastic leukemia (ALL), interactions of leukemic cells with bone marrow (BM) stroma is mediated by members of the beta1 integrin family on leukemic cells, and their respective ligands in the marrow environment, specifically VCAM-1 on the BM stromal cells and fibronectin in the extracellular matrix. In addition to serving adhesive functions, one of the ways by which integrins can transduce signals is through the activation of tyrosine kinases, and ultimately to downstream pathways which regulate specific gene expression, proliferation, and migration of cells. In a variety of cell types, integrin mediated signaling has been shown to be critical to regulation of normal and malignant cells growth and the control of apoptosis. Over the past several years we have studied beta1 integrin mediated signal transduction as it related to neoplastic pre-B cells. We have identified and focused on the major substrates, specifically a docking/adaptor protein, HEF1, which appears to be important in both oncogenic and cell adhesive signaling pathways. Moreover, HEF1 probably functions as an intermediary between tyrosine kinase dependent signal transduction pathways and cell cycle regulation through its interaction with molecules which are relevant to cell cycle control and cell differentiation. In this proposal, we plan to extend our studies of integrin signaling in ALL cells and how the molecules involved in the signaling pathways regulate cell growth and survival. To this end, we plan to undertake three specific aims. First, to investigate the role of HEF1 during integrin signaling in pre-B ALL cells. Second, to determine the consequences of modulating beta1 integrin signaling pathways on growth, survival, adhesion and migration of pre-B cell ALL cells. Third, we will examine the effect of the bone marrow stromal cell derived chemokine, SDF-1 on integrin signaling pathways and function. We hypothesize that the regulation of HEF1 phosphorylation in integrin signaling plays a central role to the regulation of ALL proliferation, survival, and migration. Understanding the cell-cell interaction between BM stromal cells and pre-B ALL cells may provide future therapeutic strategies with which to modulate the growth of these leukemias.
| Astier, A L; Svoboda, M; Hinds, E et al. (2004) Integrins regulate survival of pre-B-ALL cells through differential IAP and caspase-7 ubiquitination and degradation. Leukemia 18:873-5 |
| Astier, Anne Laurence; Xu, Ronghui; Svoboda, Marek et al. (2003) Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival. Blood 101:1118-27 |
| Sarkar, Sibaji; Svoboda, Marek; de Beaumont, Rosalie et al. (2002) The role of Aktand RAFTK in beta1 integrin mediated survival of precursor B-acute lymphoblastic leukemia cells. Leuk Lymphoma 43:1663-71 |
