Along the same lines, preclinical work with BMS-936564/MDX-1338, a therapeutic anti-human CXCR4 monoclonal antibody, revealed that this CXCR4 antagonist also induced downstream signalling (Kuhne2013). of CXCR4 antagonists is usually primarily due to CXCR4 inhibition, rather than agonistic activity, and corroborate that CXCR4 is an important target to overcome stroma-mediated drug resistance in B-ALL. 2014), and B-ALL remains one of the leading causes of person-years of life lost in the United States (362,000 years in 2010 2010)(Murphy2013). There have been major improvements in treatment outcome over the last decades with 5-year survival rates of 90% in patients below the age of 15 years although the rate is significantly lower (~40%) in adult B-ALL patients(Bhojwani and Pui 2013). Relapse has become the major challenge in the treatment of B-ALL; relapsed patients are commonly resistant to standard drugs and therefore the outcome generally is usually dismal(Fielding2007). Minimal residual disease (MRD) due to primary resistant sub-clones is considered the principal mechanism that paves the way to relapse, and the contribution of stroma-mediated drug resistance, also known as cell adhesion-mediated drug resistance (CAM-DR)(Damiano1999), has been established as a central mechanism responsible for MRD in B-ALL. Stromal cell-mediated protection of B-ALL cells is usually a mechanism adapted from normal B cell development, in which contact between precursor B cells and bone marrow stromal cells (BMSC) is critical for the survival and expansion of selected B cell progenitors. Similarly, B-ALL cells undergo rapid spontaneous apoptosis in standard suspension culture conditions, unless they are co-cultured with BMSC, indicating that BMSC are critical for B-ALL survival(Manabe1992). Furthermore, the degree of BM infiltration and MRD disease are associated with relapses and inferior prognosis in B-ALL(Brggemann2012), emphasizing that interactions between B-ALL cells and BMSC in the marrow microenvironment provide survival and drug resistance signals that should GZD824 Dimesylate be targeted for better treatment outcome. The chemokine CXCL12, previously called stromal cell-derived factor-1 (SDF-1), is usually constitutively secreted by BMSC and regulates the retention and migration of haematopoietic progenitor cells (HPC)(Peled1999), mature haematopoietic cells(Bleul1996) and various cancer cells(Burger and Kipps 2006), including B-ALL(Bradstock2000) and T-ALL(Pitt2015) cells. Besides Rabbit polyclonal to IL13RA2 being a potent chemokine, CXCL12 also has pro-survival and growth-promoting effects in normal and malignant B cells; in GZD824 Dimesylate fact, CXCL12 originally was designated pre-B-cell growth-stimulating factor, before it was recognized as a chemokine family member(Nagasawa1996a). CXCL12 GZD824 Dimesylate binds to the chemokine receptor CXCR4, a seven trans-membrane G protein coupled receptor, which is usually expressed at high levels on B-ALL cells, presumably to attract and confine B-ALL cells to BMSC. This function of CXCR4 in B cell precursors is usually further supported by CXCL12 and CXCR4 knockout (KO) mice, which have an identical phenotype with severe defects in early B lymphopoiesis, due to premature release of B cell progenitors from the marrow and their displacement into the blood(Ma1998, Nagasawa996b). Both normal B-cell precursors and B cell leukaemia cells share this mechanism for homing to CXCL12-secreting BMSC within the marrow. Clinically, high CXCR4 expression has been linked to an inferior outcome in B-ALL(Konoplev2011, van den Berk2014). Small molecule inhibitors of CXCR4 have been tested as therapeutic brokers in the pre-clinical setting(Burger and Peled 2009). For example, plerixafor (previously known as AMD3100) and BKT140 and its derivatives were shown to overcome stoma-mediated drug resistance, inhibit stroma-induced ALL cell growth/metabolism(Juarez2003) and inhibit disease progression in mouse models of B-ALL(Juarez2007). Besides inhibition of CXCR4 function, CXCR4 antagonists also can induce signalling after binding to GZD824 Dimesylate its target, CXCR4. Plerixafor and ALX40-4C have been characterized as weak partial agonists, whereas the polyphemusin derivative peptide inhibitor BKT140 was characterized as an inverse CXCR4 agonist(Zhang2002). Signalling responses induced by stimulation of CXCR4 with high concentrations of plerixafor and ALX40-4C were less robust than those seen with its natural ligand, CXCL12, and hence plerixafor and ALX40-4C were characterized as weak partial CXCR4 agonists(Zhang2002). The agonistic activity of plerixafor and ALX40-4C raises concern that some of the activity seen with CXCR4 antagonists may be due to agonistic activity, rather than blockade of CXCR4 function. Along the GZD824 Dimesylate same lines, preclinical work with BMS-936564/MDX-1338, a therapeutic anti-human CXCR4 monoclonal antibody, revealed that this CXCR4 antagonist also induced downstream signalling (Kuhne2013). The authors compared BMS-936564 with plerixafor in preclinical assays and noted marked differences; while BMS-936564 induced target cell apoptosis, plerixafor did not, suggesting that antibody binding to CXCR4 drives a signal to induce apoptosis that is impartial from inhibition of CXCL12 binding(Kuhne2013). These differences in inhibitor-induced signalling raise the question of whether some of the anti-leukaemia activity seen in prior studies may be related to agonistic activity of the CXCR4 antagonist. Therefore, we.