Targeting TIM-3 for hematological malignancy: latest updates from the 2022 ASH annual meeting.

T cell immunoglobulin domain and mucin domain-3 (TIM-3) is an important immune checkpoint (IC) protein in cancer immunosuppression that is considered a novel target for immunotherapy. Moreover, TIM-3, an immuno-myeloid regulator, is highly expressed on the cells of several solid tumors and myeloid leukemia stem cells (LSCs). TIM-3 blockade was shown to have dual effects for directly inhibiting leukemia cells and restoring T cell activation. We summarize several of the latest reports on the role of TIM-3 in immunotherapy for hematological malignancies from the 2022 ASH Annual Meeting (ASH2022).

Immediate early response 3 gene promotes aggressive progression and autophagy of AML by negatively regulating AKT/mTOR.

BACKGROUND: Immediate early response 3 (IER3) plays a vital role in many tumors. This study aims to explore the function and mechanism of IER3 in Acute myeloid leukemia (AML). METHODS: The expression of IER3 in AML was performed by bioinformatics analysis. CCK-8 proliferation assay, flow cytometry cycle assay, clone formation assay, and tumorigenic ability were used to investigate the effect of IER3 on AML cells. Unbiased label-free quantitative proteomics and label-free quantitative phosphoproteomics analysis were performed. The regulatory relationship between SATB1(Special AT-rich sequence binding protein 1) and IER3 was investigated by Real time-PCR, Western blot, Chromatin immunoprecipitation (CHIP), and PCR. RESULTS: The result indicated that the prognosis of the high IER3 expression group was significantly worse than that of the low expression group. CCK-8 assay showed that IER3 enhanced the proliferation ability. Cell cycle analysis showed IER3 could promote HL60 cells to enter the S phase of DNA synthesis from the quiescent phase. IER3 could stimulate HEL cells to enter mitosis. Clone-formation experiments suggested that IER3 enhanced clonogenic ability.IER3 promoted the tumorigenesis of AML. Further experimental investigation revealed that IER3 promoted autophagy and induced the occurrence and development of AML by negatively regulating the phosphorylation activation of AKT/mTOR pathway. SATB1 was found to bind to the promoter region of IER3 gene and negatively regulate its transcription. CONCLUSION: IER3 could promote the development of AML and induce autophagy of AML cells by negatively regulating the phosphorylation and activation of AKT/mTOR. By the way, SATB1 may negatively target regulates IER3 transcription.

Circular RNA circ-CCT3 promotes bortezomib resistance in multiple myeloma via modulating miR-223-3p/BRD4 axis.

Multiple myeloma is a frequent hematologic malignancy. Bortezomib is the first-line drug for multiple myeloma chemotherapy. The present study aimed to investigate the potential role and mechanism of circular RNA chaperonin containing TCP1 subunit 3 (circ-CCT3) in bortezomib resistance of multiple myeloma. The levels of circ-CCT3, microRNA-223-3p (miR-223-3p), and bromodomain-containing 4 (BRD4) were detected by quantitative real-time PCR or western blot. Cell Counting Kit-8 (CCK-8) method was used to measure the half-inhibitory concentration of bortezomib and cell viability. Cell cycle distribution, apoptosis, proliferation and migration were determined by flow cytometry, 5-ethynyl-2'-deoxyuridine, and wound healing assay. The levels of relevant proteins were checked via western blot. The binding association between miR-223-3p and circ-CCT3/BRD4 was validated via a dual-luciferase reporter assay. Circ-CCT3 and BRD4 were upregulated, while miR-223-3p was downregulated in bortezomib-resistant multiple myeloma patients and cells. Silencing of circ-CCT3 enhanced the sensitivity of bortezomib-resistant multiple myeloma cells to bortezomib. Circ-CCT3 knockdown weakened bortezomib resistance via modulating miR-223-3p. Moreover, miR-223-3p increased bortezomib sensitivity by inhibiting BRD4. Downregulation of circ-CCT3 attenuated bortezomib resistance of multiple myeloma via regulating miR-223-3p/BRD4 pathway, which provided a new potential target for multiple myeloma chemoresistance.

A Multi-Center, Real-World Study of Chidamide for Patients With Relapsed or Refractory Peripheral T-Cell Lymphomas in China.

Chidamide has demonstrated significant clinical benefits for patients with relapsed/refractory (R/R) PTCL in previous studies. This multi-center observational study was aimed to evaluate the objective response rate (ORR), overall survival (OS), and safety of chidamide. From February 2015 to December 2017, 548 patients with R/R PTCL from 186 research centers in China were included in the study. Among the 261 patients treated with chidamide monotherapy, ORR was 58.6% and 55 patients (21.1%) achieved complete response (CR). Among the 287 patients receiving chidamide-containing combination therapies, ORR was 73.2% and 73 patients (25.4%) achieved CR. The median OS of all patients was 15.1 months. The median OS of patients receiving chidamide monotherapy and combination therapies was 433 and 463 days, respectively. These results demonstrate a significant survival advantage of chidamide treatments as compared with international historical records. Common adverse effects (AEs) were hematological toxicities. Most AEs in both monotherapy and combined treatments were grade 1-2. No unanticipated AEs occurred. In conclusion, chidamide-based therapy led to a favorable efficacy and survival benefit for R/R PTCL. Future studies should explore the potential advantage of chidamide treatment combined with chemotherapy.

Epidemiological investigation of hemophagocytic lymphohistiocytosis in China.

BACKGROUND: Currently, most research on hemophagocytic lymphohistiocytosis (HLH) have focused on etiology and therapy, leaving few epidemiological reports. The published studies of China are mainly regional investigations. We aimed to present the overall epidemiological status of HLH in China, and provide Chinese data for the international HLH epidemiological investigation. METHODS: The data of HLH cases in China in 2019 were collected and statistically analyzed. FINDINGS: Epstein-Barr virus accounted for 44.01% of the 1445 cases in 31 regions and was the most common cause. Lymphoma-associated HLH patients were more often male (P < 0.05) while rheumatic and immune-associated HLH were more often female (P < 0.001). Primary HLH and Epstein-Barr Virus-associated HLH were predominant in children (P < 0.001) while tumor-associated HLH was predominant in adults. Lymphoma-associated HLH was positively correlated with the age of onset (P < 0.01). The diagnosis rate of 29 areas had a significant correlation with per capita Gross domestic product (P < 0.05). CONCLUSION: The different distribution of HLH etiology by age and gender contributes to the diagnosis of HLH by clinicians; The suboptimal diagnosis rate in regions with a high incidence of HLH in China is a result of the effect of the local economic level indicating the importance of improving the regional medical level.

Eukaryotic initiation factor-2, gamma subunit, suppresses proliferation and regulates the cell cycle via the MAPK/ERK signaling pathway in acute myeloid leukemia.

PURPOSE: The expression of eukaryotic translation initiation factor-2 subunit 3 (EIF2S3) in patients with non-small cell lung and colorectal cancer is lower than that in healthy individuals. However, the functions of EIF2S3 remain unclear, and its study in leukemia has not been reported. The article aims to explore the role of EIF2S3 in AML (acute myeloid leukemia) and its underlying mechanism. METHODS: Reverse transcription-quantitative PCR was performed to evaluate the expression levels of EIF2S3, and its association with patient prognosis was determined. Inducible HEL-EIF2S3 and HL-60-EIF2S3 cell lines were established by retrovirus infection. Cellular proliferation and the cell cycle were analyzed using Cell Counting Kit-8 and flow cytometric analyses. Tumorigenic ability was evaluated using xenograft nude mouse model. Gene expression profiles were analyzed in HL-60-EIF2S3 cells by next-generation sequencing, and WB analysis was performed to detect the expression of related proteins. RESULTS: The expression of EIF2S3 in patients with AML was lower than that experiencing CR (P = 0.02). Furthermore, EIF2S3 overexpression inhibited cellular proliferation, halted G0/1 to S phase cell cycle progression, and inhibited tumorigenicity (P = 0.015). 479 differentially expressed genes were identified between HL60-EIF2S3 DOX (-) and HL60-EIF2S3 DOX ( +) cells via NGS and several of them involved in MAPK/ERK signaling pathway. The phosphorylation levels of ERK decreased when EIF2S3 was overexpressed (P < 0.050). CONCLUSION: EIF2S3 overexpression may result in a decrease in cellular proliferation, cell cycle arrest, and tumorigenic inhibition via the MAPK/ERK signaling pathway in AML cells.

MicroRNA-363-3p promote the development of acute myeloid leukemia with RUNX1 mutation by targeting SPRYD4 and FNDC3B.

BACKGROUND: Runt-related transcription factor 1 (RUNX1) is one of the most frequently mutated genes in most of hematological malignancies, especially in acute myeloid leukemia. In the present study, we aimed to identify the key genes and microRNAs based on acute myeloid leukemia with RUNX1 mutation. The newly finding targeted genes and microRNA associated with RUNX1 may benefit to the clinical treatment in acute myeloid leukemia. MATERIAL/METHODS: The gene and miRNA expression data sets relating to RUNX1 mutation and wild-type adult acute myeloid leukemia (AML) patients were downloaded from The Cancer Genome Atlas database. Differentially expressed miRNAs and differentially expressed genes (DEGs) were identified by edgeR of R platform. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed by Metascape and Gene set enrichment analysis. The protein-protein interaction network and miRNA-mRNA regulatory network were performed by Search Tool for the Retrieval of Interacting Genes database and Cytoscape software. RESULTS: A total of 27 differentially expressed miRNAs (25 upregulated and 2 downregulated) and 561 DEGs (429 upregulated and 132 downregulated) were identified. Five miRNAs (miR-151b, miR-151a-5p, let-7a-2-3p, miR-363-3p, miR-20b-5p) had prognostic significance in AML. The gene ontology analysis showed that upregulated DEGs suggested significant enrichment in MHC class II protein complex, extracellular structure organization, blood vessel development, cell morphogenesis involved in differentiation, embryonic morphogenesis, regulation of cell adhesion, and so on. Similarly, the downregulated DEGs were mainly enriched in secretory granule lumen, extracellular structure organization. In the gene set enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways, the RUNX1 mutation was associated with adherent junction, WNT signaling pathway, JAK-STAT signaling pathway, pathways in cancer, cell adhesion molecules CAMs, MAPK signaling pathway. Eleven genes (PPBP, APP, CCR5, HLA-DRB1, GNAI1, APLNR, P2RY14, C3AR1, HTR1F, CXCL12, GNG11) were simultaneously identified by hub gene analysis and module analysis. MicroRNA-363-3p may promote the development of RUNX1 mutation AML, targeting SPRYD4 and FNDC3B. In addition, the RUNX1 mutation rates in patient were obviously correlated with age, white blood cell, FAB type, risk(cyto), and risk(molecular) (P < .05). CONCLUSION: Our findings have indicated that multiple genes and microRNAs may play a crucial role in RUNX1 mutation AML. MicroRNA-363-3p may promote the development of RUNX1 mutation AML by targeting SPRYD4 and FNDC3B.

COVID-19-associated coagulopathy: thromboembolism prophylaxis and poor prognosis in ICU.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities which are indicators of higher mortality especially in severe cases. METHODS: We studied patients with proven COVID-19 disease in the intensive care unit of Jinyintan Hospital, Wuhan, China from 30 to 2019 to 31 March 2020. RESULTS: Of 180 patients, 89 (49.44 %) had died, 85 (47.22 %) had been discharged alive, and 6 (3.33 %) were still hospitalised by the end of data collection. A D-dimer concentration of > 0.5 mg/L on admission was significantly associated with 30 day mortality, and a D-dimer concentration of > 5 mg/L was found in a much higher proportion of non-survivors than survivors. Sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC) scoring systems were dichotomised as < 4 or ≥ 4 and < 5 or ≥ 5, respectively, and the mortality rate was significantly different between the two stratifications in both scoring systems. Enoxaparin was administered to 68 (37.78 %) patients for thromboembolic prophylaxis, and stratification by the D-dimer concentration and DIC score confirmed lower mortality in patients who received enoxaparin when the D-dimer concentration was > 2 than < 2 mg/L or DIC score was ≥ 5 than < 5. A low platelet count and low serum calcium concentration were also related to mortality. CONCLUSIONS: A D-dimer concentration of > 0.5 mg/L on admission is a risk factor for severe disease. A SIC score of > 4 and DIC score of > 5 may be used to predict mortality. Thromboembolic prophylaxis can reduce mortality only in patients with a D-dimer concentration of > 2 mg/L or DIC score of ≥ 5.

Bioinformatics Analysis Identifies Key Genes and Pathways in Acute Myeloid Leukemia Associated with DNMT3A Mutation.

BACKGROUND: DNA methyltransferase 3 alpha (DNMT3A) mutation was one of the most frequent genetic alterations in acute myeloid leukemia (AML), which was associated with poor prognosis and appeared to be a potential biomarker. Herein, we aimed to identify the key genes and pathways involved in adult AML with DNMT3A mutations and to find possible therapeutic targets for improving treatment. METHODS: The RNA sequencing datasets of 170 adult AML patients were obtained from The Cancer Genome Atlas (TCGA) database. EdgeR of the R platform was used to identify the differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape and DAVID. And protein-protein interaction (PPI) network and clustering modules were analyzed with the STRING database and Cytoscape software. RESULTS: Mutated DNMT3A resulted in a shorter overall survival (OS) in AML patients and obviously associated with age, blast percentage in peripheral blood, and FLT3 mutation. A total of 283 DEGs were detected, of which 95 were upregulated and 188 were downregulated. GO term analysis showed that DEGs were significantly enriched in neutrophil degranulation, myeloid cell differentiation, stem cell proliferation, positive regulation of neurological system process, leukocyte migration, and tissue morphogenesis. KEGG pathway enrichment analysis indicated that the pathway of cancer, PI3K-Akt signaling pathway, and transcriptional misregulation in cancer may play a crucial role in DNMT3A mutation AML. Seven hub genes (BMP4, MPO, THBS1, APP, ELANE, HOXA7, and VWF) had a significant prognostic value. CONCLUSION: Bioinformatics analysis in the present study provided novel targets for early diagnosis and new strategies for treatment for AML with DNMT3A mutation.

Triplet Therapy with PD-1 Blockade, Histone Deacetylase Inhibitor, and DNA Methyltransferase Inhibitor Achieves Radiological Response in Refractory Double-Expressor Diffuse Large B-cell Lymphoma with 17p Deletion.

Double-expressor diffuse large B-cell lymphoma (DLBCL) with 17p deletion is an aggressive and refractory disease. Immune checkpoint blockade and epigenetic drugs have been widely used, but the efficacy of different combined applications varied. We report a case with "double-expressor" DLBCL treated with a combined regimen which consisted of programmed cell death protein 1 (PD-1) inhibitor, DNA methyltransferase inhibitor (DNMTi), and histone deacetylase inhibitor (HDACi). A 50-year-old man presented with a 6-month history of hoarseness, and 10 days of progressive shortness of breath was diagnosed of DLBCL, stage IV. The patient failed to respond to the 1st line (R-EPOCH: rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin, and dexamethasone), 2nd line (R-EPOCH + lenalidomide + ibrutinib), and a 3rd line chemotherapy combined with PD-1 inhibitor (sintilimab), decitabine, and GDP (gemcitabine, DDP, and dexamethasone). Surprisingly, patient's condition was improved after treatment with PD-1 inhibitor in combination with DNMTi/HDACi. Restaging PET revealed dramatically radiological response.

Identification of the key genes and microRNAs in adult acute myeloid leukemia with FLT3 mutation by bioinformatics analysis.

Background: Associated with poor prognosis, FMS-like tyrosine kinase 3 (FLT3) mutation appeared frequently in acute myeloid leukemia (AML). Herein, we aimed to identify the key genes and miRNAs involved in adult AML with FLT3 mutation and find possible therapeutic targets for improving treatment. Materials: Gene and miRNA expression data and survival profiles were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. EdgeR of R platform was applied to identify the differentially expressed genes and miRNAs (DEGs, DE-miRNAs). Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape and DAVID. And protein-protein interaction network, miRNA-mRNA regulatory network and clustering modules analyses were performed by STRING database and Cytoscape software. Results: Survival analysis showed FLT3 mutation led to adverse outcome in AML. 24 DE-miRNAs (6 upregulated, 18 downregulated) and 250 DEGs (54 upregulated, 196 downregulated) were identified. Five miRNAs had prognostic value and the results matched their expression levels (miR-1-3p, miR-10a-3p, miR-10a-5p, miR-133a-3p and miR-99b-5p). GO analysis showed DEGs were enriched in skeletal system development, blood vessel development, cartilage development, tissue morphogenesis, cartilage morphogenesis, cell morphogenesis involved in differentiation, response to growth factor, cell-substrate adhesion and so on. The KEGG analysis showed DEGs were enriched in PI3K-Akt signaling pathway, ECM-receptor interaction and focal adhesion. Seven genes (LAMC1, COL3A1, APOB, COL1A2, APP, SPP1 and FSTL1) were simultaneously identified by hub gene analysis and module analysis. SLC14A1, ARHGAP5 and PIK3CA, the target genes of miR-10a-3p, resulted in poor prognosis. Conclusion: Our study successfully identified molecular markers, processes and pathways affected by FLT3 mutation in AML. Furthermore, miR-10a-3p, a novel oncogene, might involve in the development of FLT3 mutation adult AML by targeting SLC14A1, ARHGAP5 and PIK3CA.

Status and prognostic nomogram of patients with Burkitt lymphoma.

The purpose of the present study was to evaluate the newest status of patients diagnosed Burkitt lymphoma (BL), an aggressive lymphoma subset with a high cure rate. Furthermore, the study aimed to create prognostic nomograms to consider various prognostic factors and estimate patient survival, paving the way for clinical decision-making. A total of 4,600 patients diagnosed with BL between 1983 and 2015 were investigated, via data collected from the SEER database. The overall status of the patients was analyzed through several aspects, including incidence and survival analysis of the previous three decades using the log-rank test and the Kaplan-Meier method. In order to construct and validate the nomograms, the patient diagnosed during 2005-2015 were randomly assigned to the training cohort and validation cohort. Univariate and multivariate analyses were applied to identify independent factors that were further included in the nomograms, predicting 3- and 5-year overall survival (OS) and cancer-specific survival (CSS). The data of the training cohort were used for internal validation and validation cohort used to external validation. C-index and calibration plots were used to validate the nomograms, comparing predicted values with actual outcomes. The incidence of BL was gradually increased from 1984 and reached its peak in 2009, at a rate of 0.491 per 100,000 [95% confidence interval (CI), 0.412-0.581]. From 2009, the incidence slowly declined year by year and dropped to 0.280 per 100,000 (95% CI, 0.224-0.346). The OS and CSS rates of patients diagnosed between 2005 and 2015 were increased, in contrast with those of patients diagnosed from 1983-1993 and 1994-2004. A total of five variables, including age, race, chemotherapy, primary site and stage, proved to be the prognostic factors of BL and were used to construct the nomograms predicting 3- and 5-year OS and CSS. The internal and external calibration plots for the probability of 3- and 5-year OS and CSS were consistent between nomogram prediction and observed outcomes. The slow decline in incidence and the significantly improved cure rate make BL a disease that is no longer an urgent problem. Effective nomograms were developed to predict the OS and CSS of patients with BL.

Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation.

BACKGROUND: Special AT-rich sequence-binding protein 1 (SATB1) is a chromatin-remodeling protein that regulates gene expressions in different types of cancer. Up-regulation of SATB1 is linked with progression of tumors. Our previous study showed that SATB1 expression was decreased in T cell leukemia/lymphoma. The contrary roles of SATB1 in solid organ tumors and hematology malignancy may provide hints to study the function of SATB1. METHODS: To characterize SATB1 mRNA and protein expression in acute myeloid leukemia (AML), we performed qRT-PCR and Western blot on bone marrow mononuclear cells from 52 newly diagnosed AML patients. Stable HL-60 cell lines with knockdown of SATB1 by shRNAs sequences (HL-60 SATB1-shRNA1 and HL-60 SATB1-shRNA2) were established. Cell proliferation, cell cycle and cell invasiveness were analyzed. Murine model was established using HL-60 SATB1-shRNAs treated nude mice and tumorigenicity was compared to study the role of SATB1 in vivo. Global gene expression profiles were analyzed in HL-60 cells with SATB1 knockdown to investigate the mechanisms underlying the regulation of AML cell growth by SATB1. RESULTS: We found that SATB1 expression was significantly decreased in patients with AML compared to normal control, and was increased after complete remission of AML. Knockdown of SATB1 enhanced the proliferation of HL-60 cells and accelerated S phase entry in vitro, and promoted the tumor growth in vivo. Global gene expression profiles were analyzed in HL-60 cells with SATB1 knockdown and the differentially expressed genes were involved in NF-κB, MAPK and PI3 K/Akt signaling pathways. Nuclear NF-κB p65 levels were significantly increased in SATB1 depleted HL-60 cells. CONCLUSIONS: Decreased SATB1 expression promotes AML cell proliferation through NF-κB activation. SATB1 could be a predictor for better response to treatment in AML.

Notch inhibition enhances graft-versus-leukemia while reducing graft-versus-host disease.

Graft-versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dissociation of graft versus-leukemia (GVL) activity from GVHD has yet to be achieved. In this study, we used γ-secretase inhibitor (GSIs, DAPT) to inhibit Notch signaling in GVHD and GVL murine model. We found that CD11c+CD80+ dendritic cells (DCs) were up-regulated but did not enhance GVHD. Regulatory T cells (Tregs) and central memory T cells that express high levels of CD62L and CD44 had an expansion after Notch inhibition. Reduced Tumor Necrosis Factor-α and increased Interferon-γ production were found, which might be ascribed to the expansion of Tregs and central memory T cells, and result in increased sensitivity of tumor cells to cytotoxic T lymphocyte activity. Fas Receptor-Fas Ligand interaction plays a critical role in GVL instead of aGVHD. Fas Ligand expressions were similar in recipients with or without Notch inhibition, suggesting that GVL activity was maintained. We showed that Notch inhibition could enhances GVL while reducing GVHD via modulating host DCs and donor T cell activity, and the production of inflammatory cytokines.

[Changes of T Cell Subsets and Their Relationship with Clinical Features and Prognosis in Patients with Acute Leukemia].

OBJECTIVE: To analyze the relationship between T cell subsets and clinical data. METHODS: mononuclear cells were collected from 103 patients with acute leukemia (AL) and 28 healthy volunteers, and percentage changes of CD3+CD4+, CD3+CD8+ and CD4+ CD25+ Foxp3+ cell subsets were assayed by flow cytometory. Relationship between the T subsets and clinical features of the patients was analyzed. RESULTS: Ratio of CD3+ T cells decreased more significantly in patients with >50% blast cells than that in patients with <50% blast cells, while the ratio of Treg between the 2 groups was not significantly different. Treg increased more statistically significantly in the patients with CD34+ leukemia cell than that with CD34- leukemia cells. In constrast to the relationship between prognosis and immune cells in the patients from 3 groups (low, intermediate and high-risk group) it was found that Treg cells increased more significantly in high-risk group than that in low-risk group. By continuously monitoring immune cells in 18 patients, it was found that Treg cells gradually increased during the first 3 courses of chemotherapy, then began to decreased in the 4th course, finally approached gradually to the normal value in the 6th course, and this change correlated with the clinical remission after chemotherapy. Treg cell number in the patients with AL was significantly higher than that in healthy controls, and Treg cell number during the onset and recurrence was significantly higher than that in the period of complete remission (continuous remission for over 6 months). Compared with the changes of immune cell number between different types of disease, it was found that Treg cells were increased more significantly in acute myeloid leukemia (AML) than that in acute lymphoblastic leukemia (ALL). Proportion of Treg cells, Treg/CD4 decreased more significantly after the 1st course of chemotherapy in the group with complete remission (CR) than that in the group without CR. The complete remission rate and recurrence rate were 68.9% and 20% respectively in the group with >10% Treg cells, while the complete remission rate and recurrence rate were 85.7% and 7.69% respectively in the group with.<10% Treg cells. In comparison of the 6 recurrent patients with 32 patients with sustained CR, it was found that the ratio of Treg cells and Treg/CD4 was increased more significantly in the patients with relapse than that with CR and in control group. CONCLUSION: Dynamic change of Treg cells in the peripheral blood was closely related with clinical feature, recurrence and prognosis in the patients with acute leukemia.

Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia.

BACKGROUND: High-mobility group AT-hook 2 (HMGA2) may serve as an architectural transcription factor, and it can regulate a range of normal biological processes including proliferation and differentiation. Upregulation of HMGA2 expression is correlated to the undifferentiated phenotype of immature leukaemic cells. However, the underlying mechanism of HMGA2-dependent myeloid differentiation blockage in leukaemia is unknown. METHODS: To reveal the role and mechanism of HMGA2 in differentiation arrest of myeloid leukaemia cells, the quantitative expression of HMGA2 and homeobox A9 (HOXA9) was analysed by real-time PCR (qRT-PCR). The regulatory function of HMGA2 in blockage of differentiation in human myeloid leukaemia was investigated through in vitro assays (XTT assay, May-Grünwald-Giemsa, flow cytometry analysis and western blot). RESULTS: We found that the expression of HMGA2 and HOXA9 was reduced during the process of granulo-monocytic maturation of acute myeloid leukaemia (AML) cells, knockdown of HMGA2 promotes terminal (granulocytic and monocytic) differentiation of myeloid leukaemia primary blasts and cell lines, and HOXA9 was significantly downregulated in leukaemic cells with knockdown of HMGA2. Downregulation of HOXA9 in myeloid leukaemia cells led to increased differentiation capacity in vitro. CONCLUSIONS: Our data suggest that increased expression of HMGA2 represents a possible new mechanism of myeloid differentiation blockage of leukaemia. Aberrant expression of HMGA2 may enhance HOXA9-dependent leukaemogenesis and myeloid leukaemia phenotype. Disturbance of the HMGA2-HOXA9 pathway is probably a therapeutic strategy in myeloid leukaemia.

Expression of the cytoskeleton regulatory protein Mena in human gastric carcinoma and its prognostic significance.

The cytoskeleton regulatory protein Mena is reportedly overexpressed in breast cancer; however, data regarding its expression level and clinical significance in gastric carcinoma (GC) is limited. The aim of the present study was to investigate Mena expression levels and prognostic significance in GC. Mena mRNA expression level was determined by reverse transcription-quantitative polymerase chain reaction in 10 paired GC and adjacent normal tissues. The Mena protein expression level was analyzed in paraffin-embedded GC samples and adjacent normal tissues by immunohistochemistry. Statistical analyses were also performed to evaluate the clinicopathological significance of Mena. The results revealed that the mRNA expression level of Mena was significantly higher in G Ct issues compared with in adjacent normal tissues from10 paired samples. In the paraffin-embedded tissue samples, the protein expression level of Mena was higher in G Ct issues compared with in adjacent normal tissues. Compared with adjacent normal tissues, Mena overexpression was observed in 52.83% (56/106) of patients. The overexpression of Mena was significantly associated with the T stage (P=0.033), tumor-node-metastasis (TNM) stage (P<0.001) and decreased overall survival (P<0.001). Based on a multivariate analysis, Mena expression level was an independent prognostic factor for overall survival time. In conclusion, Mena wasoverexpressed in G C tissues and significantly associated with the T stage, TNM stage and overall survival time. Mena may therefore be suitable as a prognostic indicator for patients with GC.

Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Expanded In Vitro for Treatment of Aplastic Anemia: A Multicenter Phase II Trial.

We conducted a phase II, noncomparative, multicenter study to assess the efficacy and safety of allogeneic bone marrow-derived mesenchymal stromal cells (BM-MSCs) expanded in vitro for patients with aplastic anemia (AA) refractory to immunosuppressive therapy. Seventy-four patients from seven centers received allogeneic BM-MSCs at a dose of 1-2 × 106 cells/kg per week for 4 weeks. Responses were assessed at 0.5, 1, 2, 3, 6, 9, and 12 months after the first cells infusion. Patients with response at 1 month continued to receive four infusions. All patients were evaluable. The overall response rate was 28.4% (95% confidence interval, 19%-40%), with 6.8% complete response and 21.6% partial response. The median times to response of leukocytic, erythrocytic, and megakaryocytic linages were 19 (range, 11-29), 17 (range, 12-25), and 31 (range, 26-84) days, respectively. After median follow-up of 17 months, overall survival was 87.8%. Seven patients developed transitory and mild headache and fever, but no other adverse events were observed. Antithymocyte globulin used in previous treatment and no activated infection throughout treatment were predictors for response. Allogeneic BM-MSCs infusion is a feasible and effective treatment option for refractory AA. The trial was registered at www.clinicaltrials.gov as NCT00195624. Stem Cells Translational Medicine 2017;6:1569-1575.

Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China.

The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.