BCL11基因与淋巴细胞肿瘤

B细胞淋巴瘤／白血病（B—cell lymphoma／leukemia，BCL）家族蛋白在细胞的增殖和抗凋亡等方面起重要作用。BCL11基因是BCL家族的新成员，包括BCL11A和BCL11B基因，近年已初步认识其结构和功能特点。不仅与淋巴细胞的发育、增殖、分化和生存密切相关，其表达异常也与淋巴细胞恶性转化有一定的关系。本文主要介绍BCL11基因特点、功能及其与淋巴细胞肿瘤等关系的最新研究进展。     

SLC7A11基因在恶性肿瘤中的研究进展

SLC7A11为溶质载体家族成员之一,该基因编码胱氨酸/谷氨酸反转运体x_c-系统的轻链亚基SLC7A11（又称xCT）。SLC7A11通过介导胱氨酸摄取和谷氨酸释放促进谷胱甘肽（glutathione,r-glutamyl cysteingl+glycine,GSH）的合成,保护细胞免受氧化应激,维持细胞的氧化还原平衡,阻止脂质过氧化诱导的细胞死亡。SLC7A11在多种恶性肿瘤中过表达,与胶质瘤、乳腺癌、卵巢癌、肝癌和肺癌等恶性肿瘤的生长、预后、转移和治疗密切相关,为恶性肿瘤新的潜在治疗靶点之一。本文就SLC7A11基因在恶性肿瘤中的研究进展进行综述。      

滤泡性淋巴瘤3B级的BCL2融合基因、BCL6分离基因及相应蛋白的表达北大核心CSCD

目的研究滤泡性淋巴瘤(follicular lymphoma,FL)3B级的形态学及细胞遗传学特征,探讨其与滤泡性淋巴瘤1-3A级和弥漫大B细胞淋巴瘤在疾病谱系上的关系。方法用荧光原位杂交技术(FISH)和免疫组织化学检测35例FL和9例生发中心B细胞(GCB)亚型弥漫大B细胞淋巴瘤中的BCL2/IGH融合基因、BCL6分离基因以及BCL2蛋白、BCL6蛋白的表达。采用SPSS13.0软件对数据进行统计分析,率的比较用卡方检验和Fisher精确检验概率法,计量资料用方差分析,P<0.05认为差异有统计学意义。相关性分析用Spearman秩相关检验。结果 FL3B级中BCL2/IGH融合发生率(27%)低于FL1-3A级(86%),差别有统计学意义(P<0.002)。该级别中BCL2蛋白表达率(45%)低于FL1-3A级(96%),差别有统计学意义(P<0.005),而与GCB的BCL2蛋白表达(22%)差别无统计学意义。各组中BCL2蛋白表达与BCL2/IGH融合、BCL6蛋白与BCL6基因分离未见相关性。结论 FL3B在形态上介于FL3A与GCB DLBCL之间,在细胞遗传学改变上更为接近GCB DLBCL,而较低的BCL2/IGH融合率提示其可能存在着一种不同于FL1-3A和GCB DLBCL的发病途径。     

多重打击B细胞淋巴瘤的研究进展

多重打击B细胞淋巴瘤是指累及MYC/8q24的染色体畸变同时伴其他一种或多种染色体异常的B细胞淋巴瘤.其中,最早发现、最常见的重现染色体畸变为累及BCL2的t（14;18）（q32;q21）,还包括MYC^＋/BCL2^＋/BCL6^＋、MYC^＋/BCL6^＋、CCND1^＋/MYC^＋、BCL3^＋/MYC＋等.文章概述了介于弥漫大B细胞淋巴瘤和伯基特淋巴瘤之间未分类淋巴瘤中的多重打击B细胞淋巴瘤,内容包括流行病学、发病机制、临床特点及预后、病理特点及治疗进展.     

嵌合抗原受体T细胞治疗B细胞淋巴瘤研究进展

B细胞淋巴瘤(BCL)是一类具有明显异质性的恶性肿瘤。近年来,随着诊疗模式的不断改进,BCL患者的缓解率有所提高,但部分患者仍然会出现复发难治的现象。嵌合抗原受体T细胞(CAR-T)是一种新疗法,目前CD19 CAR-T已被批准用于复发难治弥漫大B细胞淋巴瘤的治疗。第62届美国血液学会年会上,多项研究报道了CAR-T治疗复发难治BCL的最新进展。     

BTG/TOB抗增殖蛋白家族与肿瘤

 B细胞迁移基因/erbB2转录因子(BTG/TOB)家族是一个新的抗增殖蛋白家族。近年来研究发现BTG/TOB家族在肺癌、乳腺癌、甲状腺癌等多种肿瘤组织中表达显著缺失,并且在多种恶性肿瘤的形成和进展中起着重要作用。     

KIF11在肿瘤形成中作用机制及靶向治疗的研究进展

驱动蛋白超家族成员11(kinesin family member 11,KIF11)即驱动蛋白Eg5(kinesin-5)基因编码的纺锤体运动蛋白,是细胞分裂驱动蛋白家族的成员之一,在细胞分裂过程中参与双极有丝分裂纺锤体的形成。研究发现这类运动蛋白广泛表达,在细胞分裂和细胞内运输中发挥重要作用,这类微管相关驱动蛋白,由于其在细胞分裂中的重要生物学功能,其与肿瘤的形成关系密切,是多种恶性肿瘤的预后因子。因此KIF11也成为肿瘤靶向治疗的新靶点。本文总结了近年来对KIF11的研究进展,重点综述其结构、生物学功能与肿瘤的关系及靶向治疗。     

KLF11基因在肿瘤中的功能及作用机制

Kruppel样转录因子11（KLF11）是Kruppel样转录因子家族成员之一,参与调节细胞的增殖、周期和凋亡等多种生命活动。研究表明,KLF11基因在多种肿瘤细胞中表达量明显下调,使其抑制肿瘤细胞的作用降低。KLF11基因与肿瘤的发生和发展密切相关,对其深入研究可以更好地了解肿瘤发生和发展的机制。     

钙结合蛋白S100A11促进结直肠癌进展的作用及其机制研究

目的:探讨钙结合蛋白S100A11调控结直肠癌(colorectal cancer, CRC)进展的作用及其机制。方法:利用GEPIA、UALCAN和HPA等数据库分析S100A11在CRC中的表达情况及其与CRC临床分期和预后的关系,并利用CRC细胞系/永生化肠上皮细胞进行验证,利用RNA干扰实验进一步分析S100A11对CRC细胞迁移及CRC生物学通路的影响。结果:数据库分析结果显示,与正常结直肠组织相比,S100A11在CRC组织中表达显著升高,并且S100A11与CRC的晚期分期及不良预后密切相关。RT-qPCR和Western blot结果也显示,S100A11在CRC细胞中表达升高。敲低S100A11能够有效抑制SW480细胞的迁移和上皮间质转化(epithelial-mesenchymal transition, EMT)过程。沉默CRC细胞中S100A11的表达后,利用转录组测序和生信分析,共筛选出149个差异表达基因,这些差异表达基因的功能网络富集结果主要涉及到炎症性肠病、黏着斑和PI3K-Akt信号通路等。结论:本研究发现高表达的S100A11是CRC转移的重要因素...     

Xp11易位相关性肾细胞癌的研究进展

Xp11易位相关性肾细胞癌是存在TFE3基因易位的一种罕见肾细胞癌，与t（6；11）易位相关性肾细胞癌共同归类为MiT家族易位相关性肾细胞癌。随着免疫组织化学法、荧光原位杂交法、逆转录-聚合酶链反应以及RNA测序技术的发展和应用，越来越多的Xp11易位相关性肾细胞癌被诊断和研究，从而对于其在临床病理学、分子遗传学、临床治疗方面有了许多新的认识和进展。本文就近年来Xp11易位相关性肾细胞癌的研究进展进行综述。      

Human T‐cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T‐cells

Human T‐cell leukemia virus type 1 (HTLV‐1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T‐cell malignancy. HTLV‐1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T‐cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV‐1‐infected T‐cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV‐1‐infected T‐cells. Lentiviral transduction of Tax in a human T‐cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF‐κB, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV‐2 Tax2 protein reduced the BCL11B protein expression in T‐cells. Seven HTLV‐1‐infected T‐cell lines, including three ATL‐derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T‐cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV‐1‐infected T‐cells; Tax‐mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV‐1‐infected T‐cells.     

Multiple myeloma with t(11;14)-associated immature phenotype has lower CD38 expression and higher BCL2 dependence

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B–cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B–cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B–cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.     

Evaluation of BCL6 and MUM1 Expression in Patients with Diffuse Large B cell Lymphoma and their Correlations with Staging and Prognosis in Iran

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkins lymphoma(NHL), accounting for approximately 25% of NHL cases. The aim of this study was to evaluate the associationbetween the BCL6 and MUM1 gene expression and patient prognosis and stage. Materials and Methods: Afterethical approval, in a cross-sectional study, tissue samples of 80 patients with diffuse large B-cell lymphoma wereanalyzed for BCL6 and MUM1 gene expression. Immunohistochemical staining was performed with division intocategories of 0-5%, 5-25%, 26-50%, 51-75% and more than 75%. Other clinical and histological information suchas lymph node involvement, T-stage, B symptoms and patient outcome were also recorded. Data were analyzedwith SPSS version 16 and a P-value less than 0.05 was considered significant. Results: The patient mean agewas 46.9±10.5 years (47.6±10.7 and 46.1±9.6 for males and females, respectively). A significant association wasseen between lymphoma stage and BCL6 (p=0.045) but not MUM1 expression (p=0.09). However, the latterwas associated with mortality (p=0.006) as was also the BCL6 level (p=0.006). Conclusions: : Overexpression ofMUM1 and BCL6 is associated with poor prognosis in patients with diffuse large B-cell lymphoma.     

An in vivo genome‐wide shRNA screen identifies BCL6 as a targetable biomarker of paclitaxel resistance in breast cancer

Paclitaxel is a common breast cancer drug; however, some tumors are resistant. The identification of biomarkers for paclitaxel resistance or sensitivity would enable the development of strategies to improve treatment efficacy. A genome‐wide in vivo shRNA screen was performed on paclitaxel‐treated mice with MDA‐MB‐231 tumors to identify genes associated with paclitaxel sensitivity or resistance. Gene expression of the top screen hits was associated with tumor response (resistance or sensitivity) among patients who received neoadjuvant chemotherapy containing paclitaxel. We focused our validation on screen hit B‐cell lymphoma 6 (BCL6), which is a therapeutic target in cancer but for which no effects on drug response have been reported. Knockdown of BCL6 resulted in increased tumor regression in mice treated with paclitaxel. Similarly, inhibiting BCL6 using a small molecule inhibitor enhanced paclitaxel treatment efficacy both in vitro and in vivo in breast cancer models. Mechanism studies revealed that reduced BCL6 enhances the efficacy of paclitaxel by inducing sustained G1/S arrest, concurrent with increased apoptosis and expression of target gene cyclin‐dependent kinase inhibitor 1A. In summary, the genome‐wide shRNA knockdown screen has identified BCL6 as a potential targetable resistance biomarker of paclitaxel response in breast cancer.     

Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab

BACKGROUND:

Diffuse large B‐cell lymphomas (DLBCLs) are a biologically heterogeneous group in which various gene alterations have been reported. The aim of this study was to investigate the frequency and prognostic impact of BCL2, BCL6, and MYC rearrangements in cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R‐CHOP)‐treated DLBCL cases.

METHODS:

Tissue microarrays were constructed from 239 cases of DLBCL, and the expressions of CD10, BCL6, MUM1/IRF4, and BCL2 were evaluated by immunohistochemistry. MYC, BCL2, and BCL6 rearrangements were investigated by interphase fluorescence in situ hybridization on tissue microarrays. Survival analysis was constructed from 145 R‐CHOP–treated patients.

RESULTS:

MYC, BCL2, and BCL6 rearrangements were detected in 14 (6%), 36 (15%), and 69 (29%) of 239 DLBCL patients. Double or triple rearrangements were detected in 7 (3%) of 239 DLBCL cases. Of these, 4 had BCL2 and MYC, 2 had BCL6 and MYC, and 1 had BCL2, BCL6, and MYC rearrangements. The prognosis of these cases was extremely poor, with a median survival of 9 months. MYC rearrangement was associated with significantly worse overall survival (P = .01), especially for the cases with GC phenotype (P = .009). BCL6 rearrangement also predicted significantly shorter overall survival (P = .04), especially for the non‐GC phenotype (P = .03). BCL2 rearrangement had no prognostic impact on outcome. International Prognostic Index (P = .004) and MYC rearrangement (P = .009) were independent poor prognostic factors.

CONCLUSIONS:

Analysis of MYC gene rearrangement along with BCL2 and BCL6 is critical in identifying high‐risk patients with poor prognosis. Cancer 2012. © 2011 American Cancer Society.