B淋巴增殖性疾病的SOX11、cyclin D1、cyclin D2和cyclin D3的表达研究

目的 探讨各B淋巴增殖性疾病(B-LPD)中SOX11、cyclin D1、cyclin D2和cyclin D3表达的差异和相关性,以及与慢性淋巴细胞白血病(CLL)患者临床特征的关系.方法 采用实时定量逆转录PCR(qRT-PCR)技术检测154例B-LPD患者与12例健康对照SOX11、cyclin D1、cyc...     

Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma

Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (～25%) cases of SMZL and in 1 of 19 (～5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.     

慢性淋巴细胞白血病/小淋巴细胞淋巴瘤的研究进展

慢性淋巴细胞白血病(CLL)/小淋巴细胞淋巴瘤(SLL)为高度异质性的成熟B淋巴细胞恶性克隆性疾病.目前对于CLL/SLL的相关研究,特别是对其发病机制的更加深入的研究,以及不断完善的预后评估指标方面,均取得了较大的进展.为了给CLL/SLL的临床诊疗提供参考,笔者拟就CLL/SLL的发病机制、诊断、分期及预后评估、治疗的相关研究进展进行综述.     

Chronic lymphocytic leukemia/small lymphocytic lymphoma complicated with skin Langerhans cell sarcoma: A case report

BACKGROUNDLangerhans cell sarcoma (LCS) is a rare malignancy with poor prognosis. LCS and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) can occur in the same diseased tissues, such as lymph nodes or skin. CASE SUMMARYA 48-year-old female Han Chinese patient was admitted for generalized lymph node enlargement for 6 years and abdominal distension for 1 wk. She was diagnosed with small B-cell lymphoma (stage IV)/CLL (Benet stage B) and received chemotherapy. She started oral ibrutinib in February 2019. She was hospitalized on June 11, 2019, and a 1.5 cm × 1.5 cm dark-red nodule with ulceration scalp lesion was found. Biopsy revealed LCS but without CLL/SLL. She was diagnosed with CLL/SLL (Binet stage C, Rai stage IV) accompanied by secondary histiocytic sarcomas and skin LCS and received cyclophosphamide, doxorubicin, vincristine, dexamethasone, and etoposide but developed severe cytopenia. She ultimately refused treatments and discharged spontaneously. She died on September 12, 2019. The literature review showed that in patients with CLL/SLL, skin lesions of LCS are accompanied by CLL/SLL. This patient was different from the previously reported cases of skin LCS in patients with CLL/SLL.CONCLUSIONIn this patient, the skin lesion of LCS showed no concomitant CLL/SLL.     

Individualized Fludarabine-Based Regimen in Elderly Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Introduction  

The aim of this study was to investigate the efficacy and safety of a fludarabine-based individualized regimen in elderly patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).     

淋巴瘤白血病的病理类型与临床特征分析

目的 探讨淋巴瘤白血病(LML)患者的病理类型和临床表现.方法 按照2008年世界卫生组织(WHO)造血与淋巴组织肿瘤分类方案,回顾性分析692例非霍奇金淋巴瘤(NHL)患者中127例LML患者病理类型与临床特征.应用组织形态学、免疫组织化学、流式细胞术和骨髓检查结合临床资料进行研究.结果 15种NHL病理类型发生LML,其中发病率较高的NHL病理类型依次为B原始淋巴细胞淋巴瘤(B-LBL)、小淋巴细胞淋巴瘤(SLL)和T原始淋巴细胞淋巴瘤(T-LBL).LML的T和B细胞亚型分别为45例和74例.两组总体生存(OS)率差异有统计学意义(P＜0.01).81例患者初诊时已为LML,46例患者在病程1～88个月发展为LML,原发淋巴结内和淋巴结外者分别为96例和31例,LBL和急性淋巴细胞白血病、SLL和慢性淋巴细胞白血病有不同的发病形式和发展阶段.结论 LML并不少见.发生LML的病理类型有15种之多.其临床表现比较特殊,尤其是原发淋巴结外的LML更为独特.     

microRNA-155及microRNA-146a在慢性淋巴增殖性疾病中的表达及临床意义

目的 观察microRNA-155及microRNA-146a在慢性淋巴细胞白血病(CLL)、套区细胞淋巴瘤(MCL)及脾脏边缘区淋巴瘤(SMZL)患者CD19+B淋巴细胞中的表达,并分析其临床意义.方法 以53例CLL、13例MCL、9例SMZL患者和12名正常人为研究对象.取外周血(78份)或骨髓(9份).常规分离单个核细胞,并行CD19磁珠分选.提取CD19+细胞总RNA,应用TaqMan探针法检测microRNA-155及microRNA-146a的表达,结合患者临床资料进行统计学分析.结果 ①micro RNA-155在CLL患者中的表达(4.49±0.83)显著高于MCL(3.83 ±0.45)及SMZL(3.80±0.61)(P＜0.05);②SMZL患者中microRNA-146a的表达(3.81±0.59)显著高于CLL(2.58±0.90)及MCL(2.21±0.88)(P＜0.01);③CLL IgVH未突变组患者microRNA-155的表达显著高于突变组患者(P=0.012);④CLL患者不同细胞遗传学分组间microRNA-155及microRNA-146a的表达差异无统计学意义(P＞0.05).结论 ①不同慢性淋巴增殖性疾病(LPD)之间microRNA-155及microRNA-146a的表达存在差异;②提示microRNA可能与慢性LPD的发病甚至预后相关.     

白血病患者白细胞糖皮质激素受体及其mRNA检测结果的比较

目的对非霍奇金淋巴瘤细胞性白血病（ＮＨＬＣＬ）与急性淋巴细胞白血病（ＡＬＬ）进行鉴别诊断。方法采用放射配体结合分析法和以人糖皮质激素受体（ＧＲ）ｃＤＮＡ为探针的分子杂交技术对２２例ＮＨＬＣＬ、１８例ＡＬＬ、１０例慢性淋巴细胞白血病（ＣＬＬ）和６名健康人白细胞ＧＲ及ＧＲｍＲＮＡ进行了对比检测。结果ＮＨＬＣＬ和ＡＬＬ两类白血病患者的ＧＲ及ＧＲｍＲＮＡ水平比较,差异非常显著（Ｐ＜０．０１）;ＮＨＬＣＬ和ＣＬＬ两类白血病的ＧＲ及ＧＲｍＲＮＡ水平比较,差异不显著（Ｐ＞０．０５）。结论ＮＨＬＣＬ和ＡＬＬ两类白血病ＧＲ及ＧＲｍＲＮＡ水平的差异,对两者的鉴别诊断有重要的参考意义,两类白血病ＧＲｍＲＮＡ表达水平不同可能与细胞恶性增殖发生在不同分化阶段有关,确切机制有待进一步研究。     

Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737

Antiapoptotic B cell leukemia/lymphoma 2 (BCL2) family proteins are expressed in many cancers, but the circumstances under which these proteins are necessary for tumor maintenance are poorly understood. We exploited a novel functional assay that uses BCL2 homology domain 3 (BH3) peptides to predict dependence on antiapoptotic proteins, a strategy we call BH3 profiling. BH3 profiling accurately predicts sensitivity to BCL2 antagonist ABT-737 in primary chronic lymphocytic leukemia (CLL) cells. BH3 profiling also accurately distinguishes myeloid cell leukemia sequence 1 (MCL1) from BCL2 dependence in myeloma cell lines. We show that the special sensitivity of CLL cells to BCL2 antagonism arises from the requirement that BCL2 tonically sequester proapoptotic BIM in CLL. ABT-737 displaced BIM from BCL2's BH3-binding pocket, allowing BIM to activate BAX, induce mitochondrial permeabilization, and rapidly commit the CLL cell to death. Our experiments demonstrate that BCL2 expression alone does not dictate sensitivity to ABT-737. Instead, BCL2 complexed to BIM is the critical target for ABT-737 in CLL. An important implication is that in cancer, BCL2 may not effectively buffer chemotherapy death signals if it is already sequestering proapoptotic BH3-only proteins. Indeed, activator BH3-only occupation of BCL2 may prime cancer cells for death, offering a potential explanation for the marked chemosensitivity of certain cancers that express abundant BCL2, such as CLL and follicular lymphoma.     

126例伴骨髓侵犯的B细胞非霍奇金淋巴瘤患者染色体分析及其临床意义

目的 研究伴有骨髓侵犯的B细胞非霍奇金淋巴瘤(NHL)患者的染色体异常特点,探讨其预后意义.方法 回顾分析在我院诊断为骨髓侵犯且具有完整染色体结果的126例B细胞NHL患者的临床资料.染色体检查采取24 h短期培养法,R显带技术分析.结果 ①126例患者中弥漫大B细胞淋巴瘤(DLBCL)49例,淋巴浆细胞淋巴瘤(LPL)24例,套细胞淋巴瘤(MCL)21例,滤泡性淋巴瘤(FL)12例,边缘区淋巴瘤(MZL)11例,小细胞淋巴瘤(SLL)9例.②126例患者中52例(41.3%)患者存在染色体异常,其中克隆性染色体异常38例,非克隆性染色体异常14例.22例为单一染色体异常,30例具有两种以上染色体异常.38例具有可分析的克隆性染色体异常者中,假二倍体22例(57.9%),低二倍体6例(15.8%),超二倍体10例(26.3%).14例具有可分析的非克隆性染色体异常者中,假二倍体10例(71.4%),超二倍体4例(28.6%).DLBCL、MCL、MZL、LPL、FL、SLL患者中分别有36例(73.4%)、8例(38.1%)、4例(36.4%)、2例(8.3%)、1例(8.3%)、1例(11.1%)检出染色体异常;③克隆性染色体异常(P=0.049)、具有两种以上染色体异常(P=0.045)以及第2号(P=0.011)、3号(P=0.013)、9号(P=0.048)、11号(P=0.044)、17号(P=0.002)、18号(P=0.015)、20号(P=0.004)染色体克隆性异常为DLBCL的预后不良因素.有两种以上染色体异常(P=0.039)以及3号(P=0.028)、13号(P=0.045)染色体克隆性异常是MCL的预后不良因素.未发现特定的染色体异常与其他淋巴瘤类型的预后相关.结论 采取骨髓标本进行染色体分析,侵袭性淋巴瘤染色体异常率高于惰性淋巴瘤;以复杂核型异常为主,部分特定染色体异常有一定的预后意义.

Abstract：

Objective To study the cytogenetic characteristics of B cell non-Hodgkin' s lymphoma (B-NHL) with bone marrow involvement, and to explore the clinical significance and prognosis. Methods Clinical data of 126 B-NHL patients with bone marrow involement diagnosed in our hospital were retrospectively analyzed. Chromosome banding analysis was performed after 24 h culture. Results ①The B-NHLs included were diffuse large B-cell lymphoma (DLBCL) 38.9% (49 cases), lymphoplasmacytic lymphoma (LPL) 19% (24 cases), mantle cell lymphoma(MCL) 16.7% (21 cases), follicular lymphoma (FL) 9.5% (12 cases), marginal zone lymphoma (MZL) 8.7% (11 cases) and small lymphocytic lymphoma (SLL) 7.1% (9 cases). ②Chromosome aberrations (CA) were detected in 52 of 126 patients(41.3% ) by conventional cytogenetics( CC), including clonal CA 38 cases, and non-clonal CA 14 cases. Ploidy levels in 38 clonal CA cases were pseudodiploid (57.9%), hypodiploid ( 15.8% ) and hyperdiploid (26.3%). The incidence of chromosomal abnormalities among DLBCL, MCL, MZL, LPL, FL and SLL was 73.4%,38.1%, 36.4%, 8.3%, 8.3% and 11.1%, respectively. ③Clonal CA, CA more than two kinds, and CA of chromosomes 2, 3, 9, 11, 17, 18 and 20 were associated with shorter overall survival (OS) in DLBCL.More than two kinds of CA and CA of chromosome 3, 13 were associated with shorter OS in MCL. Conclusions The incidence of CA was higher in aggressive lymphoma than in indolent lymphoma. Complex CA were quite common, and some specific CA might have prognostic significance.     

慢性淋巴细胞白血病发生高度恶性淋巴血液病转化2例报告并文献复习

目的:增加对慢性淋巴细胞白血病转化为高度恶性淋巴血液病的认识。方法:报道两例分别转化为霍奇金淋巴瘤(混合细胞型)和弥漫大B细胞淋巴瘤的慢性淋巴细胞白血病病例,并复习相关文献。结果和结论:慢性淋巴细胞白血病在疾病进展过程中可以向多种高度恶性淋巴血液肿瘤转化:弥漫大B细胞淋巴瘤,幼淋巴细胞白血病,急性淋巴细胞白血病或霍奇金淋巴瘤等,其中以弥漫大B细胞淋巴瘤(Richter’s综合征)最为常见;病程中还可以并发多发性骨髓瘤及黑色素瘤等其他实体肿瘤。慢性淋巴细胞白血病发生血液高度恶性转化或伴发第二肿瘤均作为本病预后不良的指标,治疗效果差,生存期较单纯慢性淋巴细胞白血病显著缩短。     

Ileocolonic lymphomas: a series of 16 cases

BACKGROUND: Colonoscopic and clinical differences between primary ileocolonic mucosa-associated lymphoid tissue (MALT) lymphoma and mantle cell lymphoma (MCL) have not been defined. METHODS: We reviewed colonoscopic and clinical features in eight patients with primary MALT lymphoma and eight patients with MCL in the terminal ileum and/or colorectum. All cases were examined for CD5 and/or cyclin D1 expression. RESULTS: Endoscopic features of MALT lymphoma were characterized as protrusions that were covered with normal-appearing mucosa with or without ulceration. The gross appearances of MALT lymphomas were categorized as solitary (4 patients), multiple (3 patients), and multiple lymphomatous polyposis (MLP) (1 patient). The gross features of MCL at endoscopy were categorized as multiple protrusions (2 patients), and MLP (6 patients). The clinical stages of patients with MCL were more advanced than in patients with MALT lymphoma. CONCLUSIONS: Solitary or multiple protrusions at an early clinical stage is the most common presentation pattern of patients with MALT lymphoma, but an MLP appearance at an early stage is also possible. On the other hand, MLP appearance with an advanced clinical stage is the main presentation pattern in patients with MCL, although multiple protrusions with an early clinical stage is also possible. Histological and immunohistochemical investigation including that of cyclin D1 and CD5 expression is essential to make the final diagnosis.     

20例慢性淋巴细胞白血病临床及生物学特征研究

目的：进一步认识慢性淋巴细胞白血病（ＣＬＬ）的临床及生物学特征。方法：利用形态学、免疫学及分子遗传学检测指标分析２０例ＣＬＬ患者。结果：２０例ＣＬＬ患者中Ｔ－ＣＬＬ４例（Ｔ－大颗粒淋巴细胞白血病及ＮＫ－大颗粒淋巴细胞白血病各１例，Ｔ－ＣＬＬ／淋巴瘤２例）；Ｂ－淋巴细胞白血病１６例（Ｂ－ＣＬＬ１２例，幼稚淋巴细胞白血病１例、白血病／淋巴瘤２例、白血性淋巴浆细胞性淋巴瘤１例）。结论：形态学、免疫学及分子遗传学的诊断将对慢性淋巴细胞增殖性疾病有进一步的认识。     

套细胞淋巴瘤发病机制的研究进展

套细胞淋巴瘤(MCL)是一种侵袭性的非霍奇金淋巴瘤(NHL),该病的经典遗传学标志为t(11;14)(q13;q32)移位和细胞周期蛋白(cyclin) D1过表达,以难治和易复发为临床特征,并且总体预后不良.近年,随着对MCL细胞遗传学及分子发病机制研究的不断深入,靶向药物的开发与应用,使得该病的临床疗效有所提高.本文就近年来MCL发病机制中细胞遗传学、信号通路、转录因子、肿瘤微环境等改变的研究最新进展作一综述,旨在为MCL的早期诊断和靶向治疗提供新的方向.