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Acute myeloid leukemia

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 volume 31, pages 2336–2346 (2017)Cite this article

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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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Acknowledgements

This work was supported by grants from Biokine Therapeutics and BiolineRX.

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Authors and Affiliations

  1. Biokine Therapeutics Ltd., Ness Ziona, Israel

    M Abraham, B Bulvik, H Wald, O Eizenberg & A Peled

  2. Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel

    S Klein, I D Weiss, D Olam, L Weiss, O Wald, E Galun, S Tavor & A Peled

  3. Hematology Division, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer, Israel

    K Beider, A Avigdor, O Benjamini & A Nagler

  4. BioLineRx Ltd., Modi’in, Israel

    Y Pereg

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Correspondence to A Peled.

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Competing interests

Michal Abraham, Hanna Wald and Orly Eizenberg are employees and shareholders of Biokine Therapeutics; Amnon Peled serves as a consultant for Biokine Therapeutics and is also a shareholder. Yaron Pereg is an employee of BioLineRx. Remaining authors declare no conflict of interest.

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Abraham, M., Klein, S., Bulvik, B. et al. 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 31, 2336–2346 (2017). https://doi.org/10.1038/leu.2017.82

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