Abstract 2179 The role of SDF-1α /CXCR4 signaling in leukemia cell/bone marrow microenvironment interactions has recently been established. Activation of CXCR4 induces leukemia cell trafficking and homing into the marrow microenvironment, where the CXCR4 ligand SDF-1α is produced, keeping leukemic cells in close contact with the stromal cells and extracellular matrix that constitutively secrete growth and anti-apoptosis signals. We previously reported that CXCR4 is up-regulated under the hypoxic conditions prevalent in leukemia-harboring bone marrow niches (Fiegl M et al. Blood 2009, Konopleva M et al. ASH 2010) and that tumor-stromal interactions can be disrupted by AMD3465, a CXCR4 antagonist (Zeng et al. Blood 2009). Therefore, targeting the SDF-1α /CXCR4 axis is an attractive investigational therapeutic approach for AML. Here, we demonstrate that POL6326, a new CXCR4 antagonist developed by Protein Epitope Mimetic (PEM) Technology, can effectively antagonize SDF-1α and stromal induced chemotaxis of AML cells at concentrations as low as 200nM. By blocking CXCR4, POL6326 inhibited SDF-1α-induced activation of pro-survival signaling pathways in AML cells in vitro. Furthermore, POL6326-mediated CXCR4 inhibition partially abrogated the protective effects of stromal cells in leukemia/stromal co-culture systems. Granulocyte colony-stimulating factor (G-CSF) is known to reduce SDF-1 levels in bone marrow (Petit I et al. Nature Immunology 2002) and isoproterenol was described to mobilize hematopoietic stem cells through activation of beta-adrenergic receptors (Mendez-Ferrer S et al. Nature 2008). To evaluate the potential of POL6326 in mobilizing leukemia cells, we injected 0.5×105 Ba/F3-ITD/luc/GFP cells into NOD/SCID mice. Ten days later, POL6326 (10mg/kg, alone or in combination with isoproterenol or G-CSF) was administered to the mice subcutaneously 1 hour prior to peripheral blood collection. We found that POL6326 alone mobilized murine AML cells into circulation (21±7% increase in circulating GFP+ cells compared with PBS (p Disclosures: Ludin: Polyphor: Employment. Dembowsky: Polyphor: Employment. Andreeff: Genzyme: Consultancy; Polyphor: Research Funding.