CXCR4 Regulates Migration and Development of Human Acute Myelogenous Leukemia Stem Cells in Transplanted NOD/SCID Mice

Abstract

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 participate in the retention of normal hematopoietic stem cells within the bone marrow (BM) and their release into the circulation. Homing and engraftment of human stem cells in immunodeficient mice are dependent on cell surface CXCR4 expression and the production of BM SDF-1, which acts also as a survival factor for both human and murine stem cells. However, the role of SDF-1/CXCR4 interactions in the control of human acute myelogenous leukemia (AML) cell trafficking and disease progression is poorly understood. In this study, we report that although some AML cells do not express surface CXCR4, all AML cells tested express internal CXCR4 and SDF-1. Culture of AML cells with SDF-1 promoted their survival, whereas addition of neutralizing CXCR4 antibodies, SDF-1 antibodies, or AMD3100 significantly decreased it. Pretreatment of primary human AML cells with neutralizing CXCR4 antibodies blocked their homing into the BM and spleen of transplanted NOD/SCID/B2m null mice. Furthermore, weekly administrations of antihuman CXCR4 to mice previously engrafted with primary AML cells led to a dramatic decrease in the levels of human AML cells in the BM, blood, and spleen in a dose-and time-dependent manner. Interestingly, the same treatment did not affect significantly the levels of normal human progenitors engrafted into NOD/SCID mice. Taken together, our findings demonstrated the importance of the SDF-1/CXCR4 axis in the regulation of in vivo motility and development of human AML stem cells and identified CXCR4 neutralization as a potential treatment for AML.

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…106,108 CXCR4 receptors are functional in AML, 58,109 and surface CXCR4 expression, which is generally low when compared with lymphoid cells, correlates with functional responses, such as chemotaxis. 110 CXCR4-dependent engraftment of AML cells in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice was demonstrated by Tavor et al, 111 and this group also reported that the proteolytic enzyme elastase is involved in regulating SDF-1-dependent migration and proliferation of AML cells in vitro and in vivo. 112 CXCR4, in cooperation with VLA-4 integrins, mediates spontaneous migration of AML cells beneath MSCs, along with a decreased proliferation of migrated AML cells within stromal layers.…”

How to Establish Acute Myeloid Leukemia Xenograft Models Using Immunodeficient Mice

“…The dose of total body irradiation (TBI) depended on the mouse strains and also on the source and irradiator. It usually varied from 2 Gy to 4Gy (Chelstrom et al, 1994;Tavor et al, 2004;Liu et al, 2007;Sanchez et al, 2009). Mice should be kept in a specific pathogenfree environment with acidified water at least one week before receiving pretreatment.…”

“…Additionally, CXCR4 also influenced engraftment of human AML in the immunodeficient mice. CXCR4 played a important role in the control of human AML cell trafficking and disease progression, and CXCR4 antibodies or CXCR4 inhibitors blocked AML cells homing into the BM and spleen of transplanted mice (Tavor et al, 2004;Zhang et al, 2012b). Another study demonstrated that CXCR4 was not critical for the engraftment of AML CD34+ cells in NOD/SCID mice (Monaco et al, 2004).…”

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

“…CXCR4 and its ligand (chemokine stromal-derived factor 1a) are critical components of the stromal-leukemia cell interface. CXCR4 has an important role in cell adhesion-mediated drug resistance 100,101 and, interestingly, is found more abundantly in FLT3-ITD AML samples than in FLT3-wild-type samples. 102 CXCR4 inhibition results in disruption of AML-niche interactions and sensitizes leukemic blasts to cytotoxic chemotherapy.…”