CXCR4 Inhibitors Selectively Eliminate CXCR4 Expressing Human Acute Myeloid Leukemia Cells in NOG Mouse Model

Abstract 1881

The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates to pathogenesis is unclear. Here we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4^high (25/47; 53%) from CXCR4^neg/low (22/47, 47%) AML patients. Leukemic engraftment in NOD/Shi-scid/IL-2R^null (NOG) mice was observed for both the CXCR4^high and CXCR4^neg/low groups. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOG leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to CXCL12. Mechanisms of this anti-leukemic effect included interference with the retention of LICs with their supportive bone marrow microenvironment niches, as indicated by a mobilization of LICs in response to drugs, and increased apoptosis of leukemic cells in vitro and in vivo. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs.