Jianyi Zhu

Antileukaemia Immunity: Effect of Exosomes against NB4 Acute Promyelocytic Leukaemia Cells:

Exosomes are a family of bioactive vesicles and play important roles in antigen presentation. A recent phase I clinical trial with an exosome vaccine derived from colorectal cancer has shown minor clinical benefit. Exosomes derived from leukaemia cell lines have been little studied so, in the present study, the immunoprotective effect of exosomes secreted by NB4 cells, a human acute promyelocytic leukaemia cell line, was investigated. NB4-derived exosomes expressed the proteins retinoic acid receptor a and interstitial cell adhesion molecule 1 and contained heat shock protein 70, as demonstrated by transmission electron microscopy and Western blotting. Cytotoxicity assay demonstrated that cytotoxic T lymphocytes (CTLs) induced by dendritic cells (DCs) pulsed with exosomes were significantly more effective in killing target NB4 cells than CTLs induced by DCs alone. Exosome-based vaccines may be a promising means of prolonging disease-free survival in acute promyelocytic leukaemia patients after induction therapy.

SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: an in vitro study

BackgroundThe mechanism behind poor survival of acute myeloid leukemia (AML) patients with 1-barabinofuranosylcytosine (Ara-C) based treatment remains unclear. This study aimed to assess the pharmacogenomic effects of Ara-C metabolic pathway in patients with AML.MethodsThe genotypes of 19 single nucleotide polymorphisms (SNPs) of DCK, CDA and SLC29A1from 100 AML patients treated with Ara-C were examined. All the SNPs were screened with ligase detection reaction assay. The transcription analysis of genes was examined by quantitative real time polymerase chain reaction. The association between clinical outcome and gene variants was evaluated by Kaplan-Meier method.ResultsGenotypes of rs9394992 and rs324148 for SLC29A1 in remission patients were significantly different from those in relapsed ones. Post-induction overall survival (OS) significantly decreased in patients with the CC genotype of rs324148 compared with CT and TT genotypes (hazard ratio [HR] = 2.997 [95% confidence interval (CI): 1.71-5.27]). As compared with CT and TT genotype, patients with the CC genotype of rs9394992 had longer survival time (HR = 0.25 [95% CI: 0.075-0.81]; HR = 0.43 [95% CI: 0.24-0.78]) and longer disease-free survival (DFS) (HR = 0.52 [95% CI: 0.29-0.93]; HR = 0.15 [95% CI: 0.05-0.47]) as well As compared with CT and TT genotype, patients with the CC genotype of rs324148 had shorter DFS (HR = 3.18 [95% CI: 1.76-5.76]). Additionally, patients with adverse karyotypes had shorter DFS (HR = 0.17 [95% CI: 0.05-0.54]) and OS (HR = 0.18 [95% CI: 0.05-0.68]).ConclusionsAML patients with low activity of SLC29A1 genotype have shorter DFS and OS in Ara-C based therapy. Genotypes of rs9394992 and rs324148 may be independent prognostic predictors for the survival of AML patients.

Co-Existent de novo Myelodysplastic Syndrome and T-cell Non-Hodgkin Lymphoma: a Common Origin or Not?

The co-existence of de novo myelodysplastic syndrome (MDS) and non-Hodgkin lymphoma (NHL) prior to therapy is an extremely unusual finding. We report here a case of co-existent de novo MDS-refractory cytopenia with multilineage dysplasia and T-cell NHL, including clinical features, histopathological findings, molecular assessment, treatment course and outcomes. Other cases from the literature showing co-existence of both disorders are also reviewed; to date 19 similar cases have been reported. Among all cases (including the present patient), eight cases were diagnosed with de novo MDS and NHL simultaneously, which were considered to be true coincidences. The mechanisms responsible for the appearance of co-existence have not yet been ascertained, however in the present case a common chromosomal abnormality (20q deletion) was found in bone marrow and lymph node preparations. We conclude, therefore, that the co-existent de novo MDS and T-cell NHL seen in the present case may have a common origin.

PNAS-2: a novel gene probably participating in leukemogenesis.

Objective:As4S4 is an effective drug for the treatment of acute promyelocytic leukemia but its mechanism of action remains largely unknown. In a previous study, we identified PNAS-2, a human apoptosis-related protein gene, using gene expression profiling. In this study, we tried to clarify the role of PNAS-2 in apoptosis and leukemogenesis. Methods: NB4 and U937 leukemia cell lines and serial clinical samples were studied. RNA interference (RNAi) and RNA overexpression were used to address the potential role of PNAS-2 in apoptosis. PNAS-2 expression was examined using Northern blot in multiple tissues, and real-time PCR was applied to analyze PNAS-2 expression in various patient samples. Results: Functional analyses of PNAS-2 by RNAi and RNA overexpression indicate PNAS-2 is an anti-apoptosis gene. PNAS-2 expression is significantly increased in de novo or relapsed acute leukemia, but in patients in complete remission PNAS-2 levels decrease to levels comparable to those found in normal controls. In carcinomas, PNAS-2 expression was not upregulated, indicating that PNAS-2 overexpression was specific for leukemia. Conclusion: Based on the preliminary data, we suggest that the PNAS-2 gene functions as an anti-apoptotic gene and probably participates in leukemogenesis.

SOX12: a novel potential target for acute myeloid leukaemia

The role of SRY‐related high‐mobility‐group box (SOX) 12 in leukaemia progression and haematopoiesis remains elusive. This study aimed to examine the expression and function of SOX12 in acute myeloid leukaemia (AML) using human myeloid leukaemia samples and the acute myeloid cell line THP1. Mononuclear cells were isolated from the bone marrow of AML patients and healthy donors. SOX12 expression in haematopoietic cells was evaluated by reverse transcription polymerase chain reaction (RT‐PCR). SOX12 short hairpin RNAs (shRNAs) were transduced into THP1 cells, and gene knockdown was confirmed by quantitative RT‐PCR and Western blot analysis. SOX12 was preferentially expressed in CD34+ cells in AML patients. The THP1 cells transduced with SOX12 shRNAs exhibited significantly reduced SOX12 expression and cell proliferation. SOX12 knockdown had no effect on apoptosis, but it induced cell cycle arrest at G1 phase and reduced the number of colonies. The transduced THP1 and primary AML cells were reconstituted in non‐obese diabetic‐severe combined immunodeficient (NOD/SCID) mice, and their numbers were significantly reduced 6–12 weeks after transplantation. The mRNA and protein levels of β‐catenin were significantly diminished following SOX12 knockdown, accompanied by a decrease in TCF/Wnt activity. SOX12 may be involved in leukaemia progression by regulating the expression of β‐catenin and then interfering with TCF/Wnt pathway, which may be a target for AML.

Correlation of pretreatment 18F-FDG uptake with clinicopathological factors and prognosis in patients with newly diagnosed diffuse large B-cell lymphoma

ObjectivesThe aim of this study is to determine the correlation of pretreatment fluorine-18 fluorodeoxyglucose uptake with clinicopathological factors and its prognostic value in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients and methodsA cohort of 162 patients with newly diagnosed DLBCL who had undergone pretreatment PET/computed tomography was retrospectively reviewed. The relationship of pretreatment maximum standard uptake value (SUVmax) with clinical factors, molecular markers, and efficacy was evaluated. The value of SUVmax in predicting progression-free survival (PFS) and overall survival was analyzed. ResultsIn all, 72.9% of the patients received R-CHOP treatment; the rest received CHOP chemotherapy. The median follow-up duration was 30 months (range, 4–124 months). The median SUVmax was 12.2 (range, 1.7–42.7). SUVmax between groups differed significantly with respect to each of International Prognostic Index (IPI) factors, except for age and performance status. High SUVmax was associated with high Ki-67 and Glut-3 protein expression, but not with Glut-1. Complete remission rate differed significantly between the low (SUVmax⩽9.0) and the high SUVmax (SUVmax>9.0) groups (91.7 vs. 61.1%, P=0.000). Patients with low SUVmax showed favorable survival (3-year PFS: 92.2 vs. 63.6%, P=0.000; 3-year overall survival: 95.5 vs. 78.3%, P=0.003). On multivariate analyses, SUVmax predicted PFS independent of revised-IPI (SUVmax: P=0.011, hazard ratio 4.784; revised-IPI: P=0.004, hazard ratio 2.551). ConclusionPretreatment SUVmax was associated with clinicopathological factors, efficacy, and survival outcome. A novel prognostic model on the basis of IPI score/pretreatment SUVmax might be useful for risk stratification of patients with newly diagnosed DLBCL Video abstract: http://links.lww.com/NMC/A55.