Coexistence of BCL1/CCND1 and CMYC aberrations in blastoid mantle cell lymphoma: a rare finding associated with very poor outcome

A patient with mantle cell lymphoma (MCL) of the pleomorphic blastoid subtype is reported. The disease was clinically aggressive and refractory to chemotherapy, and the patient survived only 2 months. Cytogenetically, a t(11;19;14)(q13;q13;q32) was found. Fluorescent in situ hybridization (FISH) and molecular analyses demonstrated involvement of the BCL1/CCND1 locus in a three-way translocation. In addition, subclonal abnormalities of the region 8q24 manifested either as a t(8;22)(q24;q11)/CMYC rearrangement or trisomy 8 were identified. The pathogenetic impact of this very uncommon association of BCL1/CCND1 and CMYC rearrangements in MCL is discussed and the literature is reviewed.     

Therapeutic concepts in mantle cell lymphoma

Mantle cell lymphoma has been considered an incurable disease with current chemotherapy regimens. Recent intense chemoimmunotherapy induction regimens with or without consolidation with autologous stem cell transplantation procedures are showing a potential for cure in a sizable fraction of patients. Similarly, in the salvage setting, preliminary experience with non‐myeloablative allogeneic transplant may cure some patients even after multiple therapeutic failures. However, the recent knowledge of the three basic biologic derangements that are integrated in the disease may change the therapeutic approach of the disease in the near future. In fact, new drugs that target more specifically the major molecular alterations of the disease are being progressively incorporated into the therapeutic armamentarium of the disease. In the near future, more individualized approaches that will take into account not only risk factors present at diagnosis but also biomarkers representative of the molecular alterations present in the disease are foreseen. In this review, we are going to discuss the current therapeutic approaches and the main new drugs that target more specifically the major molecular pathways alterations of the disease.     

Properties of the mantle cell and mantle cell lymphoma.

The major lymphoid inhabitant of the follicular mantle is the mantle cell, an immunologically na?ve B cell. It is the putative cell of origin of mantle cell lymphoma (MCL), the cells of which have similar morphologic, immunophenotypic, and molecular characteristics to the normal B lymphocytes of the mantle zone. In the past year a number of advances have been made in the biology of the normal mantle cell, its interactions with the other constituents of the follicular and mantle zone microenvironments, and the development of neoplasia in this cell population. In addition, new developments in diagnostic molecular pathology have been used to more readily identify cases of MCL. The authors summarize these new advances in the understanding of the biology of the mantle cell and newer ancillary techniques in the diagnosis of lymphomas arising from this cell type.     

Histopathology of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a relatively rare lymphoma, accounting for less than 10% only of all lymphomas. Its morphology is quite homogeneous, but it varies strikingly in about 10% of the cases, making the diagnosis of MCL challenging for histopathologists. The definition of the disease was greatly influenced by the discovery of the translocation t(11;14)(q13,q32), which juxtaposes the cyclin D1 and the immunoglobulin heavy chain genes and is present in the vast majority of MCL cases. The introduction of monoclonal antibodies for the detection of cyclin D1 expression into the diagnostic procedure substantially improved the reproducibility and reliability of the pathological diagnosis. However, new challenges for histopathologists have arisen over the last years, among which are the detection of cyclin D1-negative MCL cases and clinically relevant prognostic subgroups.     

用三七总皂苷与卡维地洛治疗AMI后大鼠改善心功能作用的疗效比较与评价

目的研究三七总皂苷与卡维地洛对心肌梗死后大鼠左室心功能改善作用的疗效并比较评价。方法手术法结扎左冠状动脉前降支建立SD大鼠AMI模型36只,将模型鼠随机分为心梗对照组（AMI组）,三七总皂苷治疗组(PNS组,80 mg·kg^-1·d^-1)和卡维地洛治疗组(CARV组,6 mg·kg^-1·d^-1),每组12只;另设假结扎组（Sh组,12只）。术后24小时开始灌胃给药,4周后对各组大鼠进行超声心动图心功能和血浆脑钠肽（NT-proBNP）浓度检测。结果 （1）与Sh组比较,AMI组左室射血分数（EF）和左室收缩百分率（FS）、室间隔舒张、收缩末期厚度（IVSd、IVSs）与左室前壁收缩末期厚度（LVAWDs）均明显降低（P<0.01）,左室舒张、收缩末期内径（LVIDd、LVIDs）显著增加,且左室后壁收缩末期厚度（LVPWDs）明显增加（P<0.05）。而二尖瓣血流E/A比值下降明显;心肌运动应变率（Radial Strain Rate）减小,达峰时间（TPK,ms）明显延长;NT-proBNP浓度显著增高（P<0.01）。（2）与AMI组比较,PNS组和CARV组的EF、FS、IVSd、IVSs与LVAWDs明显增加,而LVIDd、LVIDs和LVPWDs明显降低（P<0.01）;且心肌运动应变率明显增加,达峰时间明显缩短;NT-proBNP浓度明显降低。（3）PNS组与CARV组比较,PNS组的EF、FS和LVAWDs增加显著,LVIDd、LVIDs减小明显;而IVSd、IVSs、和LVPWDs无明显差异（P>0.05）。并且,PNS组的二尖瓣血流E峰、A峰和E峰下降速率均明显增大（P<0.05）,而E/A比值和心肌应变率、达峰时间与NTproBNP浓度两组无明显差异。结论心肌梗死后大鼠的左心室收缩和舒张功能异常严重;用三七总皂苷和卡维地洛治疗4周后均能明显改善其心功能,防止心衰;但PNS在提高EF、LVAWDs和二尖瓣血流方面更优于卡维地洛。     

Essential role of TAK1 in regulating mantle cell lymphoma survival

TGF-β-activated kinase 1 (TAK1), a member of the MAPK kinase family, plays a key role in B-cell growth and development. In the present study, we examined the potential role of TAK1 as a therapeutic target for lymphoma. Here, we show that the active phosphorylated form of TAK1 is abundantly expressed in a panel of lymphoma cell lines, including mantle cell, anaplastic large cell, and Hodgkin lymphoma cell lines. Silencing TAK1 expression via the use of siRNA inhibited the activation of NF-κB and p38 and induced apoptosis in lymphoma cell lines. Moreover, submicromolar concentrations of AZ-TAK1, a novel ATP-competitive small molecule inhibitor of TAK1, dephosphorylated TAK1, p38, and IκB-α in lymphoma cell lines. These molecular events were associated with the release of cytochrome c into the cytosol, down-regulation of X-linked inhibitor of apoptosis, activation of caspase 9, and induction of apoptosis. We also demonstrate that primary lymphoma cells express TAK1 and pTAK1 and were sensitive to AZ-TAK1-mediated cell death. Collectively, our data demonstrate an essential role for TAK1 in regulating critical survival mechanisms in lymphoma and suggest that it may serve as a therapeutic target.