The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation

Abstract

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, participate in the retention of acute myeloblastic leukemia (AML) cells within the bone marrow microenvironment and their release into the circulation. AML cells also constitutively express SDF-1-dependent elastase, which regulates their migration and proliferation. To study the molecular events and genes regulated by the SDF-1/CXCR4 axis and elastase in AML cells, we examined gene expression profiles of the AML cell line, U937, under treatment with a neutralizing anti-CXCR4 antibody or elastase inhibitor, as compared with non-treated cells, using DNA microarray technology. Unsupervised hierarchical clustering analysis demonstrated similar gene expression profiles of anti-CXCR4 antibody or elastase inhibitor-treated cells, as compared with control. Pathway and functional analysis showed a greater tendency toward differentiation in cells under either one of both treatment modalities. Thus given, we further analyzed the effects of CXCR4 inhibition on AML cell growth and differentiation using the antagonist AMD3100. AMD3100 arrested proliferation in AML cell lines and triggered changes that mimicked differentiation, including morphological changes and the expression of myeloid differentiation antigens. Inhibition of elastase also triggered the differentiation of AML cells. Our study defines a new role for the SDF-1/CXCR4 axis in the regulation of leukemic cell survival and differentiation.

Interleukin-27 Inhibits the Growth of Pediatric Acute Myeloid Leukemia in NOD/SCID/Il2rg−/− Mice

“…However, these cells failed to migrate in response to the CXCR4 specific ligand, that is, CXCL12. It is of note that, in acute leukemias, the CXCL12-CXCR4 axis represents much more than a traffic controller (29), as it is important for cell survival, proliferation, and release of soluble factors (29,(46)(47)(48). The potential involvement of this pathway has not here been investigated because the CXCR4 downregulation occurred in AML cells in vivo but not in vitro, thus suggesting that this finding may be related to microenvironmental stimuli mediated by the cytokine more than a specific direct activity of IL-27 on leukemic cells.…”

Untitled

“…Moreover, activation of the SDF-1α/ CXCR4 axis is essential for the migration and survival of both normal and leukemic hematopoietic cells in vivo and in vitro [53,54]. Overexpression of CXCR4 in AML correlates with poor clinical outcome [55,56] and hence, inhibition or blockade of the SDF-1α/CXCR4 axis has become an attractive therapeutic approach for AML [57][58][59] showing efficacy in preclinical studies [60] and in an ongoing clinical trial with BL-8040 [61]. Our group demonstrated that the activation of this axis upregulates the transcription regulator Yin Yang 1 (YY1), which represses transcription of the miRNA let-7a, leading to enhanced expression of MYC and the anti-apoptotic protein BCL-XL in AML cells [62].…”

Get out—and stay out

“…4 Chronic transfusions also do not prevent radiologic progression of vascular lesions. 7 Importantly, transfusion therapy induces iron overload, which by itself can provoke organ damage, along with the risk of redcell alloimmunization. There is, therefore, an urgent need to find an equivalent or a better and more effective therapy to prevent recurrent strokes in SCA patients.…”

“…4 It is no surprise that the same molecular interactions used to retain normal hematopoietic cells in the marrow are similarly used by leukemia cells (see figure). 5 Interrupting the CXCR4/SDF-1␣ axis results in increased chemosensitization of AML cells as demonstrated both in vitro 6,7 and in vivo. 8 Thus, using agents capable of disengaging AML cells from their niche in combination with standard chemotherapeutic agents represents a novel approach to increase the exposure of leukemia cells to chemotherapy, displace them from protective niches providing growth factors, and improve on existing treatments for patients with AML.…”