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The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by downregulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression.

Abraham, M, Klein, S, Bulvik, B, Wald, H, Weiss, I D, Olam, D, Weiss, L, Beider, K, Eizenberg, O, Wald, O, Galun, E, Avigdor, A, Benjamini, O, Nagler, A, Pereg, Y, Tavor, S, Peled, A·2017·Leukemia
DOI 10.1038/leu.2017.82
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Abstract

CXCR4 is a key player in the retention and survival of human acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment. We studied the effects of the CXCR4 antagonist BL-8040 on the survival of AML blasts, and investigated the molecular mechanisms by which CXCR4 signaling inhibition leads to leukemic cell death. Treatment with BL-8040 induced the robust mobilization of AML blasts from the BM. In addition, AML cells exposed to BL-8040 underwent differentiation. Furthermore, BL-8040 induced the apoptosis of AML cells in vitro and in vivo. This apoptosis was mediated by the upregulation of miR-15a/miR-16-1, resulting in downregulation of the target genes BCL-2, MCL-1 and cyclin-D1. Overexpression of miR-15a/miR-16-1 directly induced leukemic cell death. BL-8040-induced apoptosis was also mediated by the inhibition of survival signals via the AKT/ERK pathways. Importantly, treatment with a BCL-2 inhibitor induced apoptosis and act together with BL-8040 to enhance cell death. BL-8040 also synergized with FLT3 inhibitors to induce AML cell death. Importantly, this combined treatment prolonged the survival of tumor-bearing mice and reduced minimal residual disease in vivo. Our results provide a rationale to test combination therapies employing BL-8040 and BCL-2 or FLT3 inhibitors to achieve increased efficacy of these agents.

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Metadata

Authors
Abraham, M., Klein, S., Bulvik, B., Wald, H., Weiss, I. D., Olam, D., Weiss, L., Beider, K., Eizenberg, O., Wald, O., Galun, E., Avigdor, A., Benjamini, O., Nagler, A., Pereg, Y., Tavor, S., & Peled, A.
Venue
Leukemia
Publisher
Springer Science and Business Media LLC
Published
2017-03-10
Volume
31
Issue
11
Pages
2336-2346
ISSN
  • 0887-6924
  • 1476-5551
DOI
10.1038/leu.2017.82
Cited by
104
References
2
Language
en
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CoChat. (2026). Citation check: The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by downregulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression. https://app.cochat.ai/papers/10.1038/leu.2017.82
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Abraham, M., Klein, S., Bulvik, B., Wald, H., Weiss, I. D., Olam, D., Weiss, L., Beider, K., Eizenberg, O., Wald, O., Galun, E., Avigdor, A., Benjamini, O., Nagler, A., Pereg, Y., Tavor, S., & Peled, A. (2017). The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by downregulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression. Leukemia. https://doi.org/10.1038/leu.2017.82