title: 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.
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.
authors.affiliation: Biokine Therapeutics Ltd., Ness Ziona, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Abraham
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Klein
authors.affiliation: Biokine Therapeutics Ltd., Ness Ziona, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Bulvik
authors.affiliation: Biokine Therapeutics Ltd., Ness Ziona, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Wald
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel.
authors.forename: I D
authors.initials: ID
authors.lastname: Weiss
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Olam
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Weiss
authors.affiliation: Hematology Division, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer, Israel.
authors.forename: K
authors.initials: K
authors.lastname: Beider
authors.affiliation: Biokine Therapeutics Ltd., Ness Ziona, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Eizenberg
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Wald
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Galun
authors.affiliation: Hematology Division, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Avigdor
authors.affiliation: Hematology Division, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Benjamini
authors.affiliation: Hematology Division, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Nagler
authors.affiliation: BioLineRx Ltd., Modi'in, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Pereg
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Tavor
authors.affiliation: Biokine Therapeutics Ltd., Ness Ziona, Israel.|Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Peled
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
chemical_list: C477728:4-fluorobenzoyl-TN-14003; C527276:CXCR4 protein, human; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D019718:Receptors, CXCR4; D019938:Cyclin D1; D048049:Extracellular Signal-Regulated MAP Kinases