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Background Aberrant metabolism is a hallmark of cancer cells. Recently, ATP citrate-lyase (ACLY) expression was demonstrated as an independent predictor of clinical outcome in solid tumors. However, no systematic study was conducted to explore the prognostic impact of ACLY on acute myeloid leukemia (AML). Methods To assess the prognostic value of ACLY transcript, we conducted a study with a discovery and validation design. We measured ACLY transcript by real-time quantitative PCR in 274 AML patients, and validated the prognostic value in the two independent cohorts using published data. Meta-analysis of gene-expression profile and inhibition ACLY expression in leukemia cell lines were conducted to help us understand the biological insight of low ACLY expression. Results Low ACLY expression is less common amongst AMLs with DNMT3A mutations, but coexisted in double allele CEBPA mutations. Moreover, low ACLY expression is associated with favorable overall survival in AML patients and is involved in multiple pathways. These results are also validated in two independent cohorts of AML patients. Moreover, ACLY silencing induces proliferation arrest in THP-1 and MOLM-13 leukemia cell lines. Conclusion We found low ACLY expression is associated with favorable overall survival in AML patients. Electronic supplementary material The online version of this article (10.1186/s12967-019-1884-5) contains supplementary material, which is available to authorized users.

Huntingtin interacting protein 1 (HIP1) is an endocytic protein which is overexpressed in a variety of human cancers and involved in cancer-causing translocation in leukemia. However, the prognostic impact of HIP1 expression on AML remains unclear. In this study, quantification of HIP1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 270 AML patients. As a result, high HIP1 expression was seen more frequently in older patients, M4/M5 morphology and genes of NPM1 and DNMT3A mutations, and underrepresented in favorable karyotype subgroups and CEBPA double allele mutations in our AML patients. We also found high HIP1 expressers showed lower levels of hemoglobin. In addition, overexpression of HIP1 was associated with an inferior overall survival. The prognostic value of HIP1 expression was validated in patients from an independent TCGA cohort. Notably, up-regulation of miR-16, miR-15a, miR-28 and miR-660 were seen in high HIP1 expressers from the two independent cohorts. In vitro, interfereing of HIP1 expression by siRNA suppressed the proliferation of leukemic cells, and downregulation of these miRNAs were seen in THP-1 and Kasumi cell lines after silencing HIP1 expression. In conclusion, the HIP1 gene expression might serve as a reliable predictor for overall survival in AML patients.

The prognostic value of IDH1 mutations has been systematically evaluated in acute myeloid leukemia (AML) patients recently. However, the role of IDH1 expression in AML is still under exploration. To investigate the clinical significance, we analyzed the IDH1/2 expression in 320 patients with cytogenetically normal AML (CN-AML) by quantitative real-time reverse-transcription polymerase chain reaction. High expression of IDH1 was predominant in patients with FLT3-ITD and DNMT3A mutations and less prevalent in cases with CEBPA double allele mutations. Strong association was observed between high IDH1 expression and low expression of microRNA 181 family. Prognosis was adversely affected by high IDH1 expression, with shorter overall survival and event-free survival in the context of clinical characteristics, including age, WBC count, and gene mutations of NPM1, FLT3-ITD, CEBPA, IDH1, IDH2 and DNMT3A in CN-AML. Moreover, the clinical outcome of IDH1 expression in terms of overall survival, event-free survival and complete remission rate still remained in multivariate models in CN-AML. Importantly, the prognostic value was validated using the published microarray data from 79 adult patients treated according to the German AMLCG-1999 protocol. Our results demonstrated that high IDH1 expression is associated with a poor prognosis of CN-AML.

To assess the prevalence and clinical characteristics of isocitrate dehydrogenase 1 and 2 (IDH 1 and IDH2) gene mutations in myelodysplastic syndrome (MDS) patients.Pretreatment bone marrow specimens were enriched for mononuclear cells in 108 adult patients with de novo MDS from January 2006 to August 2012. Genomic DNA was extracted from mononuclear cells. And PCR and direct sequencing were performed to sequence exon 4 of IDH gene.IDH mutations were discovered in 11 MDS patients (10.19%, 11/108) and all were heterozygous. The frequencies of IDH1 and IDH2 mutations were 5.56% (6/108) and 4.63% (5/108) respectively. Only one type of IDH1 mutation (c.394C→, p.R132C) was identified in our cohort. All IDH2 mutations caused the changes of R140 (c.419G→A, p.R140Q). However IDH2 R172 mutation was not detected. The combined mutations of IDH1 and IDH2 were not simultaneously observed in the same patient. The prevalence of IDH mutation was higher in advanced-stage MDS than those early-stage MDS patients. Mutated and wild-type groups had significantly difference in bone marrow blast percentage (median 12.5% vs 6.0%, P = 0.013) at diagnosis, but not in white blood cell count, hemoglobin level and platelet count, etc. In the normal karyotype group, the frequencies of IDH mutations were as similar as those in the abnormal karyotype group (10.61% (7/66) vs 10.00% (4/40), P0.05). The median follow-up time was 472 d, our data indicated that IDH mutations were correlated with poor overall survival (median time 512 vs 740 d, P = 0.017). IDH mutations were also an inferiorly predictive factor in the intermediate-1 group patients of International Prognostic Scoring System (IPSS) (median survival time 512 d vs not reached, P = 0.038). There was also better efficacies than other treatments in IDH mutation positive patients (median survival time 623 vs 165 d, P = 0.049).IDH mutation is a vital biomarker for better risk stratification of MDS patients with and improving IPSS. Hypomethylation agents may be effective for treating IDH mutation positive patients.

Cell differentiation agent II (CDA‑II) is a DNA methyltransferase inhibitor isolated from healthy human urine. In the present study, the antitumor activity of CDA‑II on human multiple myeloma (MM) cell lines via the mitochondrial pathway was first revealed. The human MM cell lines were exposed to CDA‑II. Cytotoxicity, caspase activation, apoptosis and the effects on the mitochondrial pathway were assessed. CDA‑Ⅱ was capable of decreasing the depolarized mitochondrial membranes and activating caspase‑3 and ‑9 and poly (ADP‑ribose) polymerase in MM cells treated with CDA‑II. CDA‑II induced caspase‑dependent cell death accompanied by a significant decrease in X-linked inhibitor of apoptosis protein (XIAP), survivin and Mcl‑1 levels. The caspase‑3 inhibitor, Z‑DEVD‑FMK, inhibited CDA‑II‑induced apoptosis. CDA‑II potently increased the Bax levels, decreased the Bcl‑2/Bax ratio and decreased the expression of the downstream targets of NF‑κB. In conclusion, the results of the present study demonstrated that CDA‑II treatment leads to the inhibition of p65 nuclear localization and potently induces caspase‑dependent apoptosis in MM cells mediated through the mitochondrial pathway at low nanomolar concentrations. These results indicate that CDA‑II is a novel inhibitor of NF‑κB activity, with notable antimyeloma efficacy. This study provides a rationale for the clinical investigation of CDA‑Ⅱ in human MM.

To explore the effect of ITF2357, a novel histone deacetylase (HDAC) inhibitor, on the growth, differentiation and apoptosis of acute myeloid leukemic (AML) cells and its mechanism.AML cell lines kasumi-1 cells as a model for AML1-ETO positive, and THP1 cells for AML1-ETO negative, the leukemic cells proliferation was analyzed by MTT assay, expression of myeloid-specific differentiation antigen and cell cycle by flow cytometry, cell apoptosis by annexin V staining and flow cytometry. AML1-ETO, acetyl-histone, and caspase protein was analyzed by Western blot.0.5 µmol/L ITF2357 treatment significantly inhibited kasumi-1 cells proliferation, with the 48 h half inhibitory concentration (IC(50)) of 0.1 µmol/L. The initial inhibitory concentration of THP1 cell line was 5 µmol/L. ITF 2357 induced apoptosis of kasumi-1 cells in a time- and dose-dependent manner. A dose-dependent increase in early apoptosis occurred at 24 hours treatment and in late apoptosis at 48 hours treatment by ITF2357. Early apoptosis cells increased from (1.44 ± 1.52)% to (24.51 ± 5.79)%. Late apoptosis cells increased from (2.37 ± 2.8)% to (63.66 ± 1.56)%. ITF2357 induced AML1-ETO degradation by caspase-dependent pathway. 0.25 µmol/L ITF2357 induced a time- and dose-dependent increase in expression of myeloid cell surface protein CD13 and CD15. 5 µmol/L ITF2357 blocked the cells at G(0)/G(1) phase, G(0)/G(1) cells increased from (39.69 ± 6.56)% to (79.2 ± 6.51)% and s-phase cells declined from (60.12 ± 3.29)% to (18.97 ± 6.62)%. Kasumi-1 cells incubated with 0.5 µmol/L of ITF2357, AML1-ETO protein began to decrease at 24 hours and could hardly be detected at 96 hours. ITF2357 induced AML1/ETO degradation through a caspase-dependent mechanism. At the same time, acetylated H3 and H4 increased.Low-dose HDAC inhibitor ITF2357 can effectively inhibit the AML cells proliferation, especially for AML1-ETO positive AML cells. It inhibits Kasumi-1 cells proliferation degradation of AML1-ETO protein expression, blocks the cells at G(0)/G(1) phase, and induces apoptosis and differentiation of the cells.

To analyze the expressed mRNA of the factor subunit A (FA) in monocyte in a hereditary factor (F) deficiency family.The F A mRNA of the proband and the other family members was analyzed by RT-PCR, semi-quantitative RT-PCR, cloning and sequencing. The three dimensional structure of the protein was predicted by SWISS-MODEL and viewed by RASMIOL.(1) A large in frame deletion from codons 11 to 279, spanning from exon 2 to 7 of F A (DelCD11-279), was identified in the proband at mRNA level and a truncated protein is predicted composed of 464 amino acids. Compared with the normal and the other families, the proband showed lower level of F A mRNA in RT-PCR. (2) SWISS-MODEL analysis showed that the truncated protein lacked the β-sandwich and a part of catalytic core, resulting in loss of the normal catalytic domains.DelCD11-279 of F A mRNA is associated with hereditary F deficiency. The reduced expressing level of F A gene is one of the causes resulting in F deficiency in the patients.

The effect of time from diagnosis to treatment (TDT) on overall survival of patients with acute myeloid leukemia (AML) remain obscure. Furthermore, whether chemotherapy delay impacts overall survival (OS) of patients with a special molecular subtype has not been investigated. Here, we enrolled 364 cases of AML to assess the effect of TDT on OS by fractional polynomial regression in the context of clinical parameters and genes of FLT3 ITD, NPM1, CEBPA, DNMT3a, and IDH1/2 mutations. Results of the current study show IDH1/2 mutations are associated with older age, M0 morphology, an intermediate cytogenetic risk group, and NPM1 mutations. TDT associates with OS for AML patients in a nonlinear pattern with a J shape. Moreover, adverse effect of delayed treatment on OS was observed in patients with IDH1/2 mutations, but not in those with IDH1/2 wild type. Therefore, initiating chemotherapy as soon as possible after diagnosis might be a potential strategy to improve OS in AML patients with IDH1/2 mutations. Disclosures No relevant conflicts of interest to declare.

Glucocorticoids are widely used chemotherapeutic agents for multiple myeloma. Drug resistance to steroid therapies is associated with the downregulation or loss of glucocorticoid receptor expression in malignant plasma cells. In this study, we examined the constitutive expression of glucocorticoid receptor in dexamethasone-sensitive and dexamethasone-resistant multiple myeloma cell lines. We found that triptolide increased the amount of the phosphorylated glucocorticoid receptor and enhanced the growth inhibitory effect of dexamethasone. Notably, these effects could not be blocked by interleukin-6, one of the most important growth factors in multiple myeloma.

AIM: To investigate the mechanism of α-fetoprotein (AFP) in escaping from the host immune surveillance of hepatoc-ellular carcinoma. METHODS: AFP purified from human umbilical blood was administrated into the cultured human lymphoma Jurkat T cell line or hepatoma cell line, Bel7402 in vitro. The expression of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and its receptor (TRAILR) mRNA were analyzed by Northern blot and Western blot was used to detect the expression of Fas and Fas ligand (FasL) protein. RESULTS: AFP (20 mg/L) could promote the expression of FasL and TRAIL, and inhibit the expression of Fas and TRAILR of Bel7402 cells. For Jurkat cell line, AFP could suppress the expression of FasL and TRAIL, and stimulate the expression of Fas and TRAILR. AFP also could synergize with Bel7402 cells to inhibit the expression of FasL protein and TRAIL mRNA in Jurkat cells. The monoclonal antibody against AFP (anti-AFP) could abolish these functions of AFP. CONCLUSION: AFP is able to promote the expression of FasL and TRAIL in hepatoma cells and enhance the expression of Fas and TRAILR in lymphocytes. These could elicit the escape of hepatocellular carcinoma cells from the host’s lymphocytes immune surveillance.