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.

The Network of Non-coding RNAs in Cancer Drug Resistance

“…In BC, lapatinib and trastuzumab are reported to regulate miR-16 via PI3K/Akt (176). Noteworthy, the altered expression of both miR-15a/16-1, due to the CXCR4 inhibitor BL-8040 induced the apoptosis of AML blasts by down-regulating ERK, BCL2, MCL1 and cyclin-D1 (177). …”

“…This miRNA plays an important role in inhibiting cell proliferation and potentiting drug effects (176). Furthermore, in leukemia miR-16 in combination with miR-15 interacts with new phase II drug (177). miR-124 has a role in neuronal differentiation (254) and may modulate resistance to gefitinib and afimoxifene: miR-124 down-regulation could reverse afimoxifene induced autophagy in BC through regulation of Beclin-1 protein (255), while in lung cancer miR-124 depletion plays a role in gefitinib resistance by regulating SNAI2 and STAT3 expressions (256).…”

Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging

“…We previously showed that up‐regulation of CXCR4 is associated with increased engraftment and motility of hematopoietic stem cells within the BM microenvironment . CXCR4 inhibition prolongs the survival of T‐ALL burdened mice, and promotes mobilization and apoptosis of AML cells . CXCR4 antagonists in combination with chemotherapy have been tested in phase 1/2 clinical trials in relapsed and refractory AML (reviewed in Cho et al .…”

“…7 CXCR4 inhibition prolongs the survival of T-ALL burdened mice, 8 and promotes mobilization and apoptosis of AML cells. [9][10][11] CXCR4 antagonists in combination with chemotherapy have been tested in phase 1/2 clinical trials in relapsed and refractory AML (reviewed in Cho et al 12 and Peled et al 13 ). These studies suggest that inhibiting CXCR4 might form an important arm of future therapeutic approaches for blood cancer of specific lineages.…”

Lösemi patogenezinde miRNA 15a/16–1 lokus delesyonlarının ve Protein L-isoaspartate O-methyltransferase (PCMT1) enziminin rolü

“…13q14.3 bölgesinde yer alan 8 gen ile (Leu-1, Leu-2, Leu-5, CLLD6, KPNA3, CLLD7, LOC51131, CLLD8) tümör oluşumu arasında DNA, RNA ve protein seviyesinde yakın bir ilişki gösterilememiş; fakat aynı bölgede bulunan miRNA 15a ve miRNA 16-1'nın KLL hastalarının büyük bir kısmında delesyona uğradığı yada downregüle edildiği belirlenmiştir (Şekil 1, [15][16][17][18][19]. Buna paralel olarak, miRNA-15a/16-1 over-ekspresyonunun akut miyeloid lösemi (AML) hücrelerinin ölümüne neden olduğu rapor edilmiştir [20]. Ayrıca, miRNA-15a/16-1 down-regülasyonunun multipl miyelom gibi farklı kanser türlerinde hücre çoğalmasını artırarak ve nöroblastom örneklerinde ilaç direncine neden olarak kötü prognoza yol açtığı gösterilmiştir [21,21].…”