Jieyu Ye

Synergistic effect of panobinostat and bortezomib on chemoresistant acute myelogenous leukemia cells via AKT and NF-κB pathways

In this study, we investigated the synergistic effects of panobinostat and bortezomib on adriamycin-resistant HL60/ADR cells and refractory acute myelogenous leukemia (AML) primary cells. Combination of both agents had synergistic cytotoxicity on these cells, and increased the sensitivity of HL60/ADR cells to adriamycin. Panobinostat plus bortezomib was shown to modulate multiple apoptotic and drug metabolic related molecules, including activation of caspases, down-regulation of XIAP, Bcl-2 and MRP1. These effects were likely to be mediated via inhibition of AKT and NF-κB pathways. These findings provide evidence for clinic protocols using panobinostat and borezomib to overcome drug resistance in refractory AML patients.

Analysis of tanshinone IIA induced cellular apoptosis in leukemia cells by genome-wide expression profiling

BackgroundTanshinone IIA (Tan IIA) is a diterpene quinone extracted from the root of Salvia miltiorrhiza, a Chinese traditional herb. Although previous studies have reported the anti-tumor effects of Tan IIA on various human cancer cells, the underlying mechanisms are not clear. The current study was undertaken to investigate the molecular mechanisms of Tan IIAs apoptotic effects on leukemia cells in vitro.MethodsThe cytotoxicity of Tan IIA on different types of leukemia cell lines was evaluated by the 3-[4,5-dimethylthiazol-2,5]-diphenyl tetrazolium bromide (MTT) assay on cells treated without or with Tan IIA at different concentrations for different time periods. Cellular apoptosis progression with and without Tan IIA treatment was analyzed by Annexin V and Caspase 3 assays. Gene expression profiling was used to identify the genes regulated after Tan IIA treatment and those differentially expressed among the five cell lines. Confirmation of these expression regulations was carried out using real-time quantitative PCR and ELISA. The antagonizing effect of a PXR inhibitor L-SFN on Tan IIA treatment was tested using Colony Forming Unit Assay.ResultsOur results revealed that Tan IIA had different cytotoxic activities on five types of leukemia cells, with the highest toxicity on U-937 cells. Tan IIA inhibited the growth of U-937 cells in a time- and dose-dependent manner. Annexin V and Caspase-3 assays showed that Tan IIA induced apoptosis in U-937 cells. Using gene expression profiling, 366 genes were found to be significantly regulated after Tan IIA treatment and differentially expressed among the five cell lines. Among these genes, CCL2 was highly expressed in untreated U-937 cells and down-regulated significantly after Tan IIA treatment in a dose-dependent manner. RT-qPCR analyses validated the expression regulation of 80% of genes. Addition of L- sulforaphane (L-SFN), an inhibitor of Pregnane × receptor (PXR) significantly attenuated Tan IIAs effects using colony forming assays.ConclusionsTan IIA has significant growth inhibition effects on U-937 cells through the induction of apoptosis. And Tan IIA-induced apoptosis might result from the activation of PXR, which suppresses the activity of NF-κB and lead to the down-regulation of CCL2 expression.

Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard-risk acute lymphoblastic leukaemia in first complete remission

We retrospectively investigated outcomes of haploidentical donor (HID) transplant for adults with standard‐risk acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) compared with human leucocyte antigen (HLA)‐matched sibling donor (MSD) and HLA‐matched unrelated donor (MUD) transplants. A total of 348 adult patients were enrolled, including 127 HID, 144 MSD and 77 MUD recipients. The cumulative incidence of grade II–IV acute graft‐versus‐host disease (aGVHD) was 39·5%, 24·0% and 40·3% for HID, MSD and MUD, respectively (P = 0·020). However, there was no difference in grade III–IV aGVHD (11·4%, 7·7%, 13·5%, respectively, P = 0·468). The 5‐year cumulative transplant‐related mortality was 16·4%, 11·6% and 19·6% (P = 0·162), the 5‐year relapse rate post‐transplantation was 14·8%, 21·1% and 16·7% (P = 0·231), the 5‐year overall survival was 70·1%, 73·7% and 69·8% (P = 0·525), and the 5‐year disease‐free survival was 68·7%, 67·3% and 63·7%, respectively (P = 0·606). Furthermore, the 3‐year GVHD‐free, relapse‐free survival was not different (50·8%, 54·9% and 52·2%, respectively, P = 0·847). Our results indicate that the outcomes of HID transplants are equivalent to those of MSD and MUD, and that HID transplantation is a valid alternative for standard‐risk adults with ALL in CR1 who lack matched donors.

The hypomethylating agent decitabine prior to chemotherapy improves the therapy efficacy in refractory/relapsed acute myeloid leukemia patients

In this study, we investigated the effect of pre-treatment with demethylating agent decitabine on susceptibility to chemotherapeutic drugs in HL60/ADR, Kasumi-1 and primary AML cells. Cytotoxic effect was increased by decitabine through activation of p53 and inhibition of c-Myc, Survivin and Bcl-2. We demonstrated in clinic that combination of decitabine and HAA consisting of harringtonine, aclarubicin and cytarabine was effective and safe to treat patients with refractory, relapsed or high-risk AML. Decitabine prior to HAA regimen improved the first induction complete response rate, and significantly prolonged overall survival and disease-free survival in these patients compared with HAA alone. These findings support clinic protocols based on decitabine prior to chemotherapy to overcome resistance and improve therapeutic efficacy in AML patients.

Association between MTHFR C677T polymorphism and risk of acute lymphoblastic leukemia: a meta-analysis based on 51 case-control studies.

Background Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk. Material/Methods The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk. Results Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79–1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80–1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84–1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73–1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81–1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed. Conclusions The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility.

Berberine acts as a putative epigenetic modulator by affecting the histone code.

Berberine, an isoquinoline plant alkaloid, exhibits a wide range of biochemical and pharmacological effects. However, the precise mechanism of these bioactivities remains poorly understood. In this study, we found significant similarity between berberine and two epigenetic modulators (CG-1521 and TSA). Reverse-docking using berberine as a ligand identified lysine-N-methyltransferase as a putative target of berberine. These findings suggested the potential role of berberine in epigenetic modulation. The results of PCR array analysis of epigenetic chromatin modification enzymes supported our hypothesis. Furthermore, the analysis showed that enzymes involved in histone acetylation and methylation were predominantly affected by treatment with berberine. Up-regulation of histone acetyltransferase CREBBP and EP300, histone deacetylase SIRT3, histone demethylase KDM6A as well as histone methyltransferase SETD7, and down-regulation of histone acetyltransferase HDAC8, histone methyltransferase WHSC1I, WHSC1II and SMYD3, in addition to 38 genes from histone clusters 1-3 were observed in berberine-treated cells using real-time PCR. In parallel, western blotting analyses revealed that the expression of H3K4me3, H3K27me3 and H3K36me3 proteins decreased with berberine treatment. These results were further confirmed in acute myelocytic leukemia (AML) cell lines HL-60/ADR and KG1-α. Taken together, this study suggests that berberine might modulate the expression of epigenetic regulators important for many downstream pathways, resulting in the variation of its bioactivities.

Superior GVHD-free, relapse-free survival for G-BM to G-PBSC grafts is associated with higher MDSCs content in allografting for patients with acute leukemia

BackgroundGranulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (G-PBSC) has largely replaced unstimulated bone marrow (un-BM) for allografting because of accelerated engraftment, but with a higher morbidity and mortality of graft-versus-host-disease (GVHD). Recent studies suggested that G-CSF-primed BM (G-BM) had similar engraftment but lower morbidity and mortality of GVHD comparing to G-PBSC. A prospective, randomized, multicenter study was conducted to compare G-BM with G-PBSC as the grafts in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemia in first complete remission (CR1).MethodsTotally 101 adult leukemia in CR1 undergoing HLA-identical sibling transplants were randomized into G-BM or G-PBSC group. The primary study endpoint was GVHD-free/relapse-free survival (GRFS).ResultsBoth the engraftment of neutrophil and platelet were 2xa0days later in G-BM than in G-PBSC group (Pu2009=u20090.412, Pu2009=u20090.39). G-BM group showed significantly lower II–IV acute GVHD (aGVHD) and similar III–IV aGVHD compared with G-PBSC group (12.2% vs 28.8% for II–IV, Pu2009=u20090.048; 4.1% vs 9.6% for III–IV aGVHD, Pu2009=u20090.267, respectively). The overall cumulative incidence of chronic GVHD (cGVHD) at 3xa0years were 22.3%u2009±u20096.3% and 44.8%u2009±u20097.6% (Pu2009=u20090.026), respectively, and extensive cGHVD were 4.5%u2009±u20093.1% and 15%u2009±u20095.3% (Pu2009=u20090.08), respectively, in G-BM and G-PBSC groups. Two groups had similar 3-year relapse, transplant-related mortality (TRM), overall survival (OS), and disease-free survival (DFS) (all Pu2009>u20090.05). G-BM group showed significantly higher probability of GRFS than G-PBSC group (73.5%u2009±u20096.3% vs 55.8%u2009±u20096.9% at 1xa0year, Pu2009=u20090.049; 69.0%u2009±u20096.7% vs 49.7%u2009±u20097.0% at 2 and 3xa0years, Pu2009=u20090.03, respectively). Graft content analysis revealed statistically higher frequency of myeloid-derived suppressor cells (MDSCs) in the G-BM than in G-PBSC grafts (Pu2009<u20090.01), and recipients received statistically higher numbers of MDSCs in G-BM than in G-PBSC group (Pu2009=u20090.045). Numbers of MDSCs infused to patients were negatively correlated with the severity of aGVHD (Pu2009=u20090.032, ru2009=u2009−0.214). Multivariate analysis showed that MDSC cell dose below the median (HRu2009=u20093.49, Pu2009<u20090.001), recipient age (HRu2009=u20092.02, Pu2009=u20090.039), and high risk of disease (HRu2009=u20092.14, Pu2009=u20090.018) were independent risk factors for GRFS.ConclusionsG-BM grafts lead a better GRFS and less GVHD associated with a higher MDSCs content compared with G-PBSC grafts.

Effect of sorafenib on the outcomes of patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation

The objective of this study was to evaluate the effect of sorafenib on the outcomes of patients with acute myeloid leukemia (AML) with FMS‐like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD) undergoing allogeneic hematopoietic stem cell transplantation (allo‐HSCT).

The protective role of MTR A2756G polymorphisms in childhood acute lymphoblastic leukemia remains inconclusive.

In a recent study published in Leukemia and Lymphoma, Xia et al . performed a meta-analysis [1] to investigate the association between MTR A2756G polymorphisms and the risk of developing childhood acute lymphoblastic leukemia (ALL). Th is meta-analysis, based on seven case – control studies, concluded that MTR A2756G is associated with decreased risk of childhood ALL, which helps to understand better the protective role of the gene in the development of childhood ALL. Th eir work should be praised. However, there are several aspects that we would like to communicate with the authors. First, in this study, the literature search was performed using three electronic databases (PubMed, ISI Web of Knowledge and the Cochrane Central Register of Controlled Trials); however, we failed to obtain the search outcomes of the Cochrane Central Register of Controlled Trials database, either in the fl owchart (their Figure 1) or in the Appendix. Besides this, a literature search for a meta-analysis without language restrictions in only three databases seems limited, and may cause a selection bias. Th erefore, more web-based databases including English (e.g. Embase, Ovid, Google Scholar, etc.) and non-English (e.g. Literatura Latino Americana em Ci ê ncias da Sa ú de [LILACS], Scientifi c Electronic Library Online [SciELO], China Academic Journals Fulltext Database [CNKI], etc.) databases should be incorporated. Second, during the review process of eligible studies, the authors excluded 42 studies due to the unavailability of full texts. We consider this inappropriate, as this reason for elimination may bring a potential risk of missing eligible literature, making the conclusions less reliable. Th erefore, if full texts are not available through databases, relevant authors should be contacted to provide original data. Th ird, an error was identifi ed in Table IV. Th e randomeff ects model was selected to compare AA versus AG GG; however, the p -value for the test of heterogeneity ( p h ) was 0.058 ( 0.05). As described in the statistical analysis section, when the p h value is x03 0.05, the fi xed-eff ects model should be used. As shown in Figure 1, the adjusted outcomes for the association test between AA and AG GG following the fi xed-eff ects model were an odds ratio (OR) (95% confi dence interval [CI]) of 0.841 (0.734, 0.965), Z value of 2.48 and p -value for Z test ( p OR ) of 0.013. p OR values of the association test for AA versus AG x02 GG diff ered signifi cantly following the diff erent eff ects models (fi xed-eff ects model, 0.013 versus random-eff ects model, 0.441). Th erefore, accurate and careful data evaluation should be performed, since we are all faced with the challenge of reproducing results from one study in another and being able to identify the real factors contributing to disease risk. It is known that childhood ALL is a multifactorial disease as a result of complex interactions between inherited genetic background and specifi c environmental exposures [2]. Previous studies investigated the role of MTR A2756G in the development of childhood ALL, and their conclusions diff er from those of the present meta-analysis. Rahimi et al . [3] concluded that MS [ MTR ] A2756G was not a risk factor for