Toll‐like receptor‐4 deficiency inhibits ultraviolet radiation‐induced tumor development by modulation of immune and inflammatory responses

Ultraviolet (UV) B irradiation of the skin induces acute inflammation, as characterized by erythema, edema, and immunosuppression, and is subsequently linked to the progression of skin cancer. Toll‐like receptor 4 (TLR4), a component of innate immunity, has been shown to play an important role in cancer. To elucidate the role of TLR4 in UVB‐induced tumor development, TLR4‐proficient (C3H/HeN) and TLR4‐deficient (C3H/HeJ) mice were exposed to multiple doses of UVB radiation (200 mJ/cm²) for 40 weeks. Photocarcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared with TLR4‐proficient mice, whereas significantly greater numbers of tumors occurred in TLR4‐proficient mice. There was significant upregulation of inflammatory markers like COX‐2, PGE₂, S100A8, and S100A9 in the skin of TLR4‐proficient mice than the skin of TLR4‐deficient mice. Furthermore, we found that TLR4‐proficient mice had a significantly higher number of Gr1+CD11b+ myeloid cells CD4+CD25+ regulatory T‐cells than TLR4‐deficient mice. Furthermore, the levels of interferon (IFN)‐γ cytokine was increased and the levels of interleukin (IL)‐4, IL‐10, and IL‐17 cytokines were decreased in serum, skin, and tumor lysates of TLR4‐deficient mice in comparison with samples from TLR4‐proficient mice. Together, our data indicate that TLR4‐mediated inflammation may cause suppression of antitumor responses and trigger the development of UVB‐induced skin cancers. Thus, strategies to inhibit TLR4‐mediated immune suppression may allow us to develop preventive and therapeutic approaches for the management of UVB‐induced cutaneous tumors.     

Selective targeting of Toll‐like receptors and OX40 inhibit regulatory T–cell function in follicular lymphoma

Immunotherapeutic strategies are promising approaches for the treatment of follicular lymphoma (FL). However, their efficacy may be limited by immunosuppressive elements in the immune system and tumor microenvironment. Therefore, strategies to reverse the effects of the immunosuppressive elements are needed. We observed that regulatory T cells (Tregs) were increased in the peripheral blood at diagnosis and persisted in high numbers after induction of clinical remission with a cyclophosphamide and doxorubicin‐containing chemotherapy regimen in FL patients. High levels of peripheral blood Tregs prior to therapy were associated with decreased progression‐free survival in FL patients treated with either chemotherapy or combination immunotherapy that targeted CD20 and PD‐1 with monoclonal antibodies rituximab and pidilizumab, respectively. Intratumoral and peripheral blood Tregs potently suppressed autologous antitumor effector T cells in FL. However, the effects of FL Tregs could be reversed by triggering Toll‐like receptors (TLR) with TLR ligands Pam₃CSK4 (TLR 1/2), flagellin (TLR 5), and CpG‐B (TLR 9), and/or OX40. The TLR ligands synergized with each other as well as OX40 signaling to inhibit Tregs. Furthermore, they restored the function of FL tumor‐specific effector T cells. Our results suggest that a state of tolerance exists in FL patients at diagnosis and after induction of clinical remission, and agents that activate TLRs 1/2, 5, and 9, and OX40 may serve as adjuvants to enhance the efficacy of antitumor immunotherapeutic strategies and preventive vaccines against infectious diseases in these patients.     

Expression of activating natural killer‐cell receptors is a hallmark of the innate‐like T‐cell neoplasm in peripheral T‐cell lymphomas

Peripheral T‐ or natural killer (NK)‐cell lymphomas are rare and difficult‐to‐recognize diseases. It remains arduous to distinguish between NK cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK‐cell receptors and examined the expression using immunohistochemistry in 22 cases with T‐ and NK‐cell neoplasms comprising angioimmunoblastic T‐cell lymphoma, anaplastic lymphoma kinase (ALK)‐positive and ‐negative anaplastic large‐cell lymphomas, extranodal NK/T‐cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T‐cell lymphoma, aggressive NK‐cell leukemia, and other peripheral T‐cell lymphomas. Inhibitory receptor leukocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK‐cell receptors were expressed predominantly in TIA‐1‐positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK‐cell neoplasms and cytotoxic T‐lymphocyte‐derived lymphomas including monomorphic epitheliotropic intestinal T‐cell lymphoma. One Epstein‐Barr virus‐harboring cytotoxic T‐lymphocyte‐derived lymphoma mimicking extranodal NK/T‐cell lymphoma, nasal type lacked these NK‐cell receptors, indicating different cell origin from NK and innate‐like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log‐rank test, P = .024). We propose that the presence of activating NK‐cell receptors may provide new insights into understanding peripheral T‐cell lymphomas and characterizing them as innate‐like T‐cell neoplasm.     

Negative prognostic impact of low absolute CD4+ T cell counts in peripheral blood in mantle cell lymphoma

Tumor microenvironment and host immunity are closely related to outcome in patients with mantle cell lymphoma (MCL). However, few researchers have focused on the prognostic value of peripheral blood lymphocyte subsets counts. The purpose of this study was to investigate the prognostic value of lymphocyte subsets and absolute monocyte counts. Sixty‐eight patients were analyzed retrospectively. Absolute CD4⁺ T cell counts (ACD4C), CD8⁺ T cell counts, nature killer cell counts, and CD4/CD8 ratios were assessed by peripheral blood flow cytometry and correlated with clinical parameters and long‐term outcomes. The median follow‐up for all patients was 21 months and the median survival time was 44 months. The overall survival (OS) rate at 1, 3, and 5 years was 80%, 51%, and 41%, respectively. In our cohort, high absolute monocyte count, and low ACD4C and CD4/CD8 ratio were associated with unfavorable OS (P = 0.029, P = 0.027, and P = 0.045, respectively) by univariate analysis. Multivariate analysis indicated that low ACD4C was a significant predictor of unfavorable OS (P = 0.004) independent of the simplified MCL International Prognostic Index (P = 0.048) in patients treated with or without rituximab (P = 0.011). Low CD4⁺ T cell counts proved to be a significant predictor of unfavorable OS in patients with MCL.     

Concomitant high expression of Toll‐like receptor (TLR) and B‐cell receptor (BCR) signalling molecules has clinical implications in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive disease with frequent relapse. Targeted therapies against B‐cell receptor (BCR) molecules have demonstrated improved outcomes in relapsed cases. However, clinical responses are slow and selective, with failure to attain complete remission in a significant subset of patients. Complex interaction of BCR signal transduction with toll‐like receptor (TLR) and other pathways in MCL remains unknown, thus averting progress in development of targeted therapies. We have performed detailed digital quantification of BCR/TLR signalling molecules and their effector pathways in a cohort (n = 81) of MCL patients and correlated these data with overall survival. Hierarchical clustering model based on BCR/TLR genes revealed two distinct (BCR^high and BCR^low) subsets of patients (n = 32; 40%) with significant differences in expression (>1.5‐fold change; p < 0.05). Higher levels of BTK/SYK/BLNK/CARD11/PLCG signalosome and lower expression of MALT1/BCL10 genes suggested tonic pattern of BCR activation. Amplified expression of TLR6/TLR7/TLR9 was noted in concert with hyper‐responsiveness of BCR machinery. MYD88, a key TLR adaptor molecule, was not upregulated in any of these clusters, which may suggest a ‘cross‐talk’ between BCR and TLR pathways. In sync with BCR/TLR signalling, we recorded significantly enhanced expression of genes associated with NF‐kB pathway in BCR^high subset of MCL patients. On univariate analysis, the BCR^high patients showed a trend towards inferior clinical response to a standardized treatment protocol, compared with the BCR^low group (log rank, p = 0.043). In conclusion, we have identified hyperactive BCR/TLR signalling pathways and their effector downstream targets in a subset of MCL patients and associated it with poor clinical outcomes. Our study provides quantitative evidence at RNA expression level of possible concomitant collaboration between TLR and BCR signalling molecules in MCL. These data will provide further insights for future functional studies and, hence, development of targeted therapies for MCL patients. Copyright © 2015 John Wiley & Sons, Ltd.     

Serum beta‐2 microglobulin as a prognostic biomarker in patients with mantle cell lymphoma

Although serum beta‐2 microglobulin (B2M) has been suggested as a prognostic factor for mantle cell lymphoma (MCL), additional data are necessary to confirm its role. Between November 2005 and July 2014, a total of 52 patients with MCL were identified from the database of Asan Medical Center, Seoul, Korea. Pretreatment serum B2M information was available in 50 patients (96%). Overall survival (OS) was compared according to the serum B2M level with a cut‐off value of 2.5 mg/L. The median MCL international prognostic index (MIPI) score was 5.84 (range 4.72–7.80), and the median biologic MIPI (MIPI‐b) score was 6.27 (4.93–8.47). Pretreatment serum B2M was elevated in 30 patients (60%) and was significantly related to advanced stage (p = 0.02) and high MIPI (p = 0.03) and MIPI‐b (p = 0.03) scores. With median follow‐up duration of 29.8 months (range 0.8–87.0 months), the median OS was 56.2 months [95% confidence interval (CI) 36.6‐75.9 months] in all patients, and serum B2M was significantly associated with OS (p = 0.001). In multivariate analyses adjusted for MIPI or MIPI‐b scores and rituximab, elevated serum B2M was significantly associated with poor OS (when adjusting MIPI, hazard ratio = 26.4, 95% CI 2.9–241.3, p = 0.004; when adjusting MIPI‐b, hazard ratio = 20.1, 95% CI 2.4–170.1, p = 0.006). Thus, pretreatment serum B2M may be an independent and significant prognostic factor in patients with MCL. Copyright © 2015 John Wiley & Sons, Ltd.     

Inhibitors of BCR signalling interrupt the survival signal mediated by the micro‐environment in mantle cell lymphoma

Several studies provide evidences for mantle cell lymphoma (MCL) cell survival relying on B‐cell receptor (BCR)‐mediated signalling pathways, whereas the nature of this activation is unknown. Significant progress in MCL treatment is achieved through therapies targeting BCR‐associated kinases, i.e., Ibrutinib and Fostamatinib, inhibitors of BTK and SYK, respectively. Our study addresses survival signals emanating from the BCR or the tumour environment and how inhibiting BCR signalling effectors might impact these survival signals. We found that BTK was constitutively activated and that SYK phosphorylation was highly increased and sustained upon BCR activation of primary MCL cells. Moreover, MCL cells from leukaemic patients secreted high amount of IL‐1β, IL‐6, IL‐8 and CCL5. Activation of the BCR induced (i) cell survival, (ii) STAT3 activation and (iii) increased autocrine secretion of IL‐1β, IL‐6, IL‐8, CCL5, IL‐10, TNFα and VEGF. Specific inhibition of BTK by Ibrutinib or SYK by Fostamatinib (R406) reversed these protective effects and decreased both basal and BCR‐induced autocrine cytokine secretions associated with STAT3 phosphorylation. Interestingly, targeting BTK and SYK prevented and inhibited BCR‐induced MCL cell adhesion to human bone marrow stromal cells (HMSCs) in short‐ and long‐term co‐culture. We demonstrated that BCR‐induced survival relies on autocrine secretion of IL‐1β, TNFα and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis.     

Radiotherapy in mantle cell lymphoma: A literature review

Mantle cell lymphoma (MCL) is a B-cell malignancy, comprising between 3% and 10% of all adult-onset non-Hodgkin lymphomas. MCL is considered incurable with current treatment modalities and most patients require multiple lines of treatment during their lifetime. MCL is very sensitive to radiotherapy (RT), even when delivered in low doses. In limited-stage MCL, RT can enable the de-escalation of systemic therapy. RT monotherapy is a valid option for frail patients. In advanced-stage disease, RT is very potent mode of palliation, even in heavily pretreated and chemo-resistant patients. Furthermore, it can provide a respite during which systemic treatment is unnecessary. In general, RT has a favorable toxicity profile and can be repeated as necessary for local relapse or distant disease. This effective, safe, and relatively inexpensive modality of therapy has been underutilized for patients with MCL. In this review, we will outline the use of RT for limited and advanced-stage disease and its potential application in combination with novel drugs.     

Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B‐cell‐derived mantle cell lymphoma

Composite lymphomas (CL) represent the occurrence of two distinct lymphomas in the same patient. Often, CL share a common cellular origin, thus representing a unique model to investigate the multistep genetic path leading to lymphomagenesis in general and to the specific development of each distinct lymphoma component in particular. Here, we present the molecular analysis of a case consisting of an unusual Hodgkin lymphoma (HL) and a mantle cell lymphoma (MCL), intimately admixed within one another in lymph nodes and bone marrow yet phenotypically distinct, in a patient who first presented with splenic/leukemic MCL two years earlier. MCL and Hodgkin and Reed/Sternberg (HRS) cells harbored identical immunoglobulin (Ig) V_H gene rearrangements with shared somatic mutations, proving their common clonal origin from a (post‐)germinal center (GC) B cell. This also demonstrates the (post‐)GC origin of MCL with mutated IgV genes. Both lymphomas carried the same CCND1/IGH translocation and, unexpectedly for HL, expressed cyclin D1 and OCT2. Thus, HRS cells are able to preserve IGH locus activity (otherwise usually silenced in HL) to promote expression of an oncogene translocated into this locus. Both lymphoma populations further showed an identical TP53 function‐impairing mutation, and later acquired a TP53 heterozygous deletion independently from one another (convergent evolution). The surprisingly close genetic relationship of the lymphomas, together with their histological intermingling and the clinical history of the patient, suggests subclonal evolution of HL from MCL as a plausible pathway in alternative to that so far described in CL, i.e. separate development from a common precursor.     

Pharmacokinetic profile and first preliminary clinical evaluation of bendamustine in Taiwanese patients with heavily pretreated indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Prior studies found bendamustine is efficacious in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL). To date, no studies have reported the efficacy of bendamustine in a Chinese population. This multicentre phase II trial evaluated the pharmacokinetics (PK), safety and efficacy of bendamustine monotherapy in Chinese patients in Taiwan with pretreated indolent B‐cell NHL or mantle cell lymphoma (MCL). For PK assessments, patients were randomized (n = 16; 11 with indolent B‐cell NHL and five with MCL) to 90 or 120 mg/m² of bendamustine for the first cycle. Plasma levels of bendamustine and its two metabolites were analyzed. For efficacy and safety evaluations, bendamustine 120 mg/m² was given to all patients every 3 weeks starting at cycle 2 for a minimum of a total of six cycles. The median age of patients was 61.7 years, and the majority were men (75%). The median number of prior treatments was 4 (range, 1–9 regimens), and all patients were previously treated with rituximab. Bendamustine plasma concentration peaked near the end of infusion and was rapidly eliminated with a mean elimination half‐life (t_1/2) of 0.67–0.8 h. Of the evaluable patients (n = 14), the overall response rate was 78.6%, including 7.2% of patients having a complete response. Mean progression‐free survival was 27.5 weeks. The most common grade 3–4 adverse events were leucopenia (56.3%), neutropenia (56.3%) and thrombocytopenia (25%). In conclusion, bendamustine was efficacious and well tolerated in Taiwanese patients with indolent NHL and MCL with a similar PK profile to that of other populations. Copyright © 2014 John Wiley & Sons, Ltd.     

Outcome of mantle cell lymphoma patients treated at a single institution over the past decade

Mantle cell lymphoma (MCL) is a rare non‐Hodgkin's lymphoma entity with a heterogeneous clinical presentation. Various therapeutic considerations in MCL for younger and elderly patients were used over the past decade. We retrospectively analyzed all 44 patients consecutively treated in a tertiary hospital between 2000 and 2010 with newly diagnosed MCL. Patient characteristics, treatment regimens and biological markers were evaluated with regard to overall survival (OS). Treatment regimens were categorized into internationally accepted intensive standard therapies and less intensive alternative treatment regimens given with palliative intent. Biological markers were correlated with clinical outcome by univariate analysis. The median age of the entire study group was 66 years (range: 42–88), with 23 (52%) patients ≥65 years. Thirty‐one (70%) patients received standard regimens, the remaining 13 (30%) patients were treated with other, less intensive regimens with palliative intent. With a median follow‐up of 5.25 years, the three‐year OS rate was 60% [95% confidence interval (CI) 0.47–0.77]. Patients treated with standard regimens had a three‐year survival rate of 77% (range: 64–94%). Of these, patients younger than 65 years were observed to have better OS (83% at 3 years; 95% CI 68–100%) than those older than 65 years (69% at 3 years; 95% CI 48–99%). In univariate analysis, the only parameters with a statistically significant prognostic impact on OS were absolute monocyte count as a continuous variable, lactate dehydrogenase and absolute lymphocyte count (>0.5 × 10⁹/l) at diagnosis. In conclusion, our data of an unselected group of patients with newly diagnosed MCL treated at a single centre tertiary hospital are in line with results from larger randomized trials demonstrating an improved OS rate of younger as well as elderly MCL patients within the last decade. Copyright © 2013 John Wiley & Sons, Ltd.     

miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma

B-cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. We revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR-17-92 cluster target genes, we performed pulldown-seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead-coated streptavidin, and quantified using next-generation sequencing. The pulldown-seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR-19b), CDKN2A (miR-17), SYNE1 (miR-20a), TET2 (miR-18, miR-19b, and miR-92a), TNFRSF10A (miR-92a), and TRAF3 (miR-17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.     

套细胞淋巴瘤诊疗进展

套细胞淋巴瘤（mant lecell lymphoma ,MCL ）是一种少见的B 细胞非霍奇金淋巴瘤（non-Hodgkin's lymphoma,NHL ）类型,兼具有惰性淋巴瘤和侵袭性淋巴瘤的临床病理特点。目前MCL 的临床治疗仍然是以全身化疗为主,含有阿糖胞苷的强诱导化疗,随后行自体造血干细胞移植（autologous stem cell transplantation,Auto-HSCT ）巩固,可以显著延长生存期,但MCL 仍然属于不可治愈的淋巴瘤类型。近年来,随着对MCL 发病机制的深入研究,更多的新药如Btk抑制剂、PI 3K 抑制剂、免疫调节剂等在MCL 中得到应用。初治、复发难治MCL 都具有更多的治疗选择,如何将新药和现有的化疗更为有机的结合,更好的改善MCL 患者的生存期是未来研究的重点。     

套细胞淋巴瘤的诊治进展

套细胞淋巴瘤(MCL)是一组以t(11;14)和细胞周期蛋白D1阳性(cyclinD1 )过度表达为特征的侵袭性非霍奇金淋巴瘤(NHL),约占NHL发病的5%~8%,预后差,近期通过比较基因组杂交(CGH),基因芯片和蛋白质组分析等研究MCL取得令人关注的进展。化疗 利妥昔治疗使治疗有效率较前明显提高,异体或自体干细胞移植亦使MCL的预后大为改善,新的治疗方案如蛋白酶体抑制剂硼替佐米(borte-zomib),反应停 利妥昔,细胞周期依赖激酶抑制剂(flavopridol)及哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂CCI-779等的疗效令人鼓舞。     

R‐High‐CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY

Although induction immunochemotherapy including high‐dose cytarabine and rituximab followed by high‐dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R‐High‐CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20‐65 years. Patients received 1 cycle of R‐High‐CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R‐High‐CHOP/CHASER. Primary endpoint was 2‐year progression‐free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38‐65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty‐five patients completed ASCT. Two‐year PFS was 77% (80% CI 68‐84), which met the primary endpoint. Five‐year PFS and overall survival were 52% (95% CI 34‐68%) and 71% (95% CI 51‐84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R‐High‐CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.     

Expression of nucleic acid‐sensing Toll‐like receptors predicts HPV16 clearance associated with an E6‐directed cell‐mediated response

Toll‐like receptors (TLRs), important in rapid clearance of incident human papillomavirus (HPV) infections, may also be important in shaping the adaptive response to persistent infections. We examined here the association between TLR expression and clearance of HPV16 infections following periods of persistence, using longitudinal TLR measurements and a time‐to‐clearance analysis, as well as the interaction between TLRs and adaptive, cell‐mediated responses involved in clearance. TLR2, TLR3, TLR7, TLR8 and TLR9 mRNA expression were measured in cervical cytobrush samples by quantitative PCR. Responses to the HPV16 E6 and E7 oncoproteins were measured by an interferon‐γ immunospot assay. Bivariable and multivariable Cox proportional hazard models were used to estimate the effect of TLRs on HPV16 clearance. Higher expression of TLR3 or TLR7 at an HPV16‐positive visit was a significant (p ≤ 0.05) predictor of clearance by the following visit, in both unadjusted and adjusted (for smoking and oral contraceptive use) models. In women with, but not those without, a positive response to E6, higher expression of TLR3 (hazard ratio: 1.2 [95% confidence interval: 1.04–1.39], p = 0.012), TLR7 (1.39 [1.14–1.7], p = 0.001), TLR8 (1.37 [1.11–1.69], p = 0.003), or TLR9 (1.53 [1.13–2.08], p = 0.006) was significantly associated with clearance, revealing an important link between innate and adaptive immunity in the control of HPV infections following periods of persistence.     

An overlapping case of in situ mantle cell neoplasia and leukemic non-nodal mantle cell lymphoma

In situ mantle cell neoplasia (isMCN) and leukemic non-nodal mantle cell lymphoma (nnMCL) are classified as an indolent subtype of mantle cell lymphoma (MCL). The tumor cells of isMCN are restricted to the inner layer of the lymphoid tissue mantle zone, exhibiting an in situ pattern histologically. On the other hand, nnMCL is distributed in the peripheral blood, bone marrow and sometimes the spleen, but lymphadenopathy or systemic organ involvement is rare. We report a case of isMCN in a submandibular lymph node resected from a 65-year-old Japanese male. The tumor cells were positive for cyclin D1 (CCND1) and SOX11 expression, and were restricted to the mantle zone area of the lymph node. However, tumor cells were also detected in the stomach mucosa, bone marrow tissue and peripheral blood, suggesting nnMCL. isMCN and nnMCL may have a partly overlapping disease spectrum, although the correlation between these two subtypes has not been well described. This present case demonstrated characteristics overlapping between isMCN and nnMCL.     

miR-150在套细胞淋巴瘤中的表达及意义

  目的   探讨套细胞淋巴瘤（mantle cell lymphoma,MCL）中miR-150的表达情况及其临床意义。   方法   通过定量RT-PCR检测29例初治MCL患者及7例正常人外周血B细胞中miR-150和c-Myc的表达水平,探索miR-150和c-Myc表达之间的关系;利用RNAi阻断MCL细胞系Mino和HBL-2中c-Myc表达后,检测miR-150的变化,确定c-Myc是否参与miR-150的表达调控;抑制P493-6细胞表达c-Myc后,观察miR-150的变化,进一步明确miR-150是否受c-Myc调节;将pre-miR-150电转HBL-2细胞系,通过集落形成试验明确miR-150对细胞增殖的影响,Western blot检测c-Myb蛋白的变化。   结果   与正常人外周血B细胞相比,MCL患者低表达miR-150、过表达c-Myc,两者的表达呈负相关;阻断c-Myc后,Mino和HBL-2细胞的miR-150表达增加;抑制c-Myc表达后,P493-6细胞的miR-150表达增高;过表达miR-150后,HBL-2的c-Myb蛋白表达水平和集落形成能力下降。   结论   MCL患者低表达miR-150的原因可能与其c-Myc过表达有关。miR-150能够抑制MCL的增殖,在MCL的治疗中具有潜在价值。