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T-cell acute lymphoblastic leukaemia （T-ALL） is a challenging malignancy with a high relapse rate attributed to drug resistance. Tetrandrine （TET）, a bisbenzylisoquinoline alkaloid extracted from a Chinese herb, is a potential anti-cancer and anti-leukaemic drug. In this study we investigated the mechanisms of TET resistance in T-ALL cells in vitro. Among the four T-ALL cell lines tested, Jurkat and CEM ceils exhibited the lowest and highest resistance to TET with IC50 values at 24 h of 4.31±0.12 and 16.53±3.32 pmol/L, respectively. When treated with TET, the activity of transcription factor activator protein 1 （AP-1） was significantly decreased in Jurkat cells but nearly constant in CEM cells. To avoid cell-specific variation in drug resistance and transcription factor activities, we established a TET-R Jurkat subclone with the estimated IC50 value of 10.90±92 pmol/L by exposing the cells to increasing concentrations of TET. Interestingly, when treated with TET, TET-R Jurkat cells exhibited enhanced AP-1 and NF-κB activity, along with upregulation of c-Jun N-terminal kinase （JNK） and extracellular signal-regulated kinase （ERK） signaling pathways, whereas the expression of P-gp was not altered. Selective inhibition of JNK but not ERK suppressed AP-1 activity and TET resistance in TET-R Jurkat cells and in CEM cells. These results demonstrate that Jurkat cells acquire TET resistance through activation of the JNK/AP-1 pathway but not through P-gp expression. The JNK/AP-1 pathway may be a potential therapeutic target in relapsed T-ALL.

Current approaches for the treatment of chronic lymphocytic leukemia （CLL） have greatly improved the prognosis for survival, but some patients remain refractive to these therapeutic regimens. Hence, in addition to reducing the long-term side- effects of therapeutics for all leukemia patients, there is an urgent need for novel therapeutic strategies for difficult-to-treat leukemia cases. Due to the cytotoxicity of drugs, the major challenge currently is to deliver the therapeutic agents to neoplastic cells while preserving the viability of non-malignant ceils. In this study, we propose a therapeutic approach in which high doses of hydroxychloroquine and chlorambucil were loaded into biodegradable polymeric nanopartides coated with an anti-CD20 antibody.We first demonstrated the ability of the nanoparticles to target and internalize in tumor B-cells. Moreover, these nanoparticles could kill not only p53-mutated]deleted leukemia cells expressing a low amount of CD20, but also circulating primary ceils isolated from chronic lymphocytic leukemia patients. The safety of these nanoparticles was also demonstrated in healthy mice, and their therapeutic effects were shown in a new model of aggressive leukemia. These results showed that anti-CD20 nanoparticles containing hydroxychloroquine and chlorambucil can be effective in controlling aggressive leukemia and provided a rationale for adopting this approach for the treatment of other B-cell disorders.

Background：The postremission therapics for adult patients generally contain consolidation chemotherapy,allogeneic hematopoietic stem cell transplantation and autologous hematopoietic stem cell transplantation （auto-HSCT）.Because of the various results from different centers,the optimal therapy for adult acute lymphoblastic leukemia （ALL） patients is still uncertain.This study aimed to better understand predictive factors and role of auto-HSCT in the postremission thcrapy for adult ALL patients.Methods：The outcomes of 135 adult patients with ALL,who received the first auto-HSCT in Hematopoietic Stem Cell Transplantation Center of Blood Diseases Hospital,Chinese Academy of Medical Sciences from January 1,1994 to February 28,2014,were retrospectively analyzed.Survival curves were estimated using the Kaplan-Meier method and simultaneous effects of multiple covariates were estimated with the Cox model.Results：Overall survival （OS） and disease-free survival （DFS） at 5 years for the whole cohort were 59.1 ± 4.5% and 59.0 ± 4.4%,respectively.The cumulative nonrelapse mortality and relapse rate at 5 years were 4.5 ± 0.03% and 36.6 ± 0.19%.For both OS and DFS,acute T-cell lymphoblastic leukemia,high lactate dehydrogenase （LDH） at diagnosis,blast cell proportion ≥5% on the 15th day of induction therapy,and extramedullary infiltration before HSCT were the poor prognosis factors.In addition,age ≥35 years predicted poor DFS.Only T-ALL and high LDH were the independent undesirable factors associated with OS and DFS in Cox regression model.For 44 patients who had results of pretransplantation minimal residual disease （MRD）,positive MRD （MRD ≥0.01%） indicated poor OS （P =0.044） and DFS （P =0.008）.Furthermore,for the standard risk group,the patients with negative MRD （MRD 〈0.01%） had better results （OS at 18 months was 90.0 ± 9.5%,while for the patients with positive MRD OS was 50.0 ± 35.4%,P =0.003;DFS at 18 months was 90.0 ± 9.5%,while for the positive MRD group DFS was 0%,P 〈 0.001）.Conclusions：This study confirmed that auto-HSCT combined with posttransplantation maintenance chemotherapy could be an option for adult ALL patients and pretransplantation MRD may play a significant role in the direction of therapy for adult ALL patients.

Aim： To examine the effects of triptolide （TPL） on T-cell leukemia cells and identify their underlying mechanisms. Methods： The cytotoxicity of TPL was assessed by MTT assay. Cell apoptosis was determined using annexin V and DAPI staining and analyzed by flow cytometry or fluorescence microscopy. The activation of caspase pathways and the expression of nuclear factor KB （NF-KB） p65 were examined by Western blotting. Differences in microRNA （miRNA） expression in Molt-4 and Jurkat cells before and after TPL treatment were identified using microarrays and real-time RT-PCR, respectively. Results： TPL 20-160 nmol/L treatment potently inhibited cell growth and induced apoptosis in T-cell lymphocytic leukemia cell lines. Molt-4 and Jurkat cells, however, were more sensitive to TPL than L428 and Raji cells. After 24 h of treatment, bortezomib abrogated the growth of Molt-4 and Jurkat cells with an IC5o of 15.25 and 24.68 nmol/L, respectively. Using Molt-4 cells, we demonstrated that TPL 20-80 nmol/L inhibited the translocation of NF-κB p65 from the cytoplasm to the nucleus and that phosphorylated NF-KB p65 in nuclear extracts was down-regulated in a dose-dependent manner. Similar results were also seen in Jurkat cells but not in L428 cells, as these cells are resistant to TPL and bortezomib （a NF-κB inhibitor）. Twenty-three miRNAs were differentially expressed after TPL treatment. Functional analysis revealed that TPL treatment could inhibit expression of miR-16-1＊ and that transfection of miR-16-1＊ led to significantly decreased apoptosis induced by TPL. Conclusion： Our in vitro studies suggest that TPL might be an effective therapeutic agent for treatment of T-cell lymphocytic leukemia and that its cytotoxic effects could be associated with inhibition of NF-KB and down-regulation of miR-16-1＊.

To the Editor：Large granular lymphocytic leukemia （LGLL） is a rare chronic clonal lymphoproliferative disease characterized by a persistent increase in large granular lymphocytes,which are large lymphocytes with a low nucleus to cytoplasm ratio and an abundant cytoplasm with azurophilic granules.

DNA methyl-transferase 3A (DNMT3A) mutation has recently been identified as an independent risk factor for patients with acute myeloid leukemia (AML). However, reports are scanty on its rate and subsequent impact on patients with acute lymphoblastic leukemia (ALL), especially in Chinese population. In this study, we investigated the incidence and prognostic implication of DNMT3A mutation in 57 Chinese adult ALL patients. A total of 3 (5.3%) T-ALL cases were found to have the DNMT3A R882H mutation, which was significantly greater than that found in B-ALL subtype (P=0.048). The patients aged between 40 and 60 years old had higher mutation rate than other age groups (P=0.042). Patients with DNMT3A mutation had shorter overall survival (OS) than their wild-type counterparts. Our study demonstrated that Chinese ALL patients might develop DNMT3A mutation, which exerts a negative impact on their prognosis. These findings might help in risk stratification and treatment choice for Chinese ALL patients.

The variable heavy chain region (VH) genes of 3 untreated patients with B-cell chronic lymphocytic leukemia (B-CLL) were cloned and analyzed. The VH family used was VH3-11, VH3-72 and VH3-33. More than 2% difference from the corresponding germline gene was detected in all the 3 obtained potential functional genes (average 16.7). Mutation pattern analysis indicated evidence of antigen selective pressure observed in 1 of 3 cases. Our findings suggested that the tumor cells originate from post-GC cells.