TLX1 and NOTCH coregulate transcription in T cell acute lymphoblastic leukemia cells

Background  

The homeobox gene TLX1 (for T-cell leukemia homeobox 1, previously known as HOX11) is inappropriately expressed in a major subgroup of T cell acute lymphoblastic leukemia (T-ALL) where it is strongly associated with activating NOTCH1 mutations. Despite the recognition that these genetic lesions cooperate in leukemogenesis, there have been no mechanistic studies addressing how TLX1 and NOTCH1 functionally interact to promote the leukemic phenotype.     

Nasal-type NK/T cell lymphoma: clinical features and treatment outcome

Nasal-type NK/T cell lymphoma is an increasingly recognised disease entity of aggressive clinical behaviour. The objective of this study was to investigate clinical features and treatment outcomes in patients with nasal-type NK/T cell lymphoma. From January 1991 to December 2003, 26 patients diagnosed as nasal-type NK/T cell lymphoma were included in the analysis. One half of patients presented with poor performance status (ECOG > or =2); 46% of patients were categorised as high intermediate or high-risk group according to IPI; and 46% of patients were diagnosed at advanced stage. The median survival for 26 patients with nasal-type NK/T cell lymphoma was 7.4 months (95% CI, 0.1, 16.9). The treatment outcome of primary anthracycline-based chemotherapy was poor: 60% CR rate in localised disease and 0% CR rate in advanced disease. After a median follow-up of 24.4 months (range 3.1-99.0) in patients with localised disease who had achieved a CR (range 29.6-165.7), three patients (50.0%) developed disease recurrence at 6.1, 21.8, and 52.1 months, respectively, and all patients presented with locoregional failure. The predictive factors for poor survival were of age greater than 60, advanced stage and poor performance in multivariate analysis. In conclusion, Nasal-type NK/T cell lymphomas showed a poor response to the conventional anthracycline-based chemotherapy, and thus an investigation for an innovative therapy is urgently needed to improve survival in these patients.     

PTEN、MLL基因在T淋巴母细胞淋巴瘤／白血病的表达及其意义

 目的　分析肿瘤抑制基因PTEN、混合系白血病（MLL）基因等在T淋巴母细胞淋巴瘤／白血病（T-LBL／ALL）的表达及意义。方法　选用76例T-LBL／ALL患者淋巴结存档蜡块,应用免疫组织化学EnVision法进行PTEN标记,用20例反应性增生淋巴结标本作正常对照。并用荧光原位杂交（FISH）技术检测MLL基因所在11q23染色体的断裂和扩增情况。结果　76例T-LBL／ALL中,PTEN的表达率为64.47 %（49／76）,低于淋巴结反应性增生的100 %（20／20）（χ2＝19.220,P＜0.05）。PTEN表达与临床分期、Ki-67、乳酸脱氢酶（LDH）呈负相关（P＜0.05）。76例T-LBL／ALL中,MLL基因发生11q23染色体断裂13例（17.11 %）,扩增18例（23.68 %）。MLL基因断裂组总体生存率（25.0 %）低于非断裂组（43.6 %）（χ2＝11.357,P＜0.05）。MLL基因扩增组总体生存率（17.1 %）低于非扩增组（42.7 %）（χ2＝4.533,P＜0.05）。结论　抑癌基因PTEN表达降低在T-LBL／ALL的发生发展中可能具有重要作用。MLL基因发生染色体11q23断裂和扩增有助于对T-LBL／ALL预后的判断,发生MLL基因断裂或扩增的T-LBL／ALL预后较差,提示MLL基因断裂或扩增可能为T-LBL／ALL的一种分子亚型。     

PTEN、MLL基因在T淋巴母细胞淋巴瘤/白血病的表达及其意义

Objective To investigate the significance and expression of PTEN, MLL in T lymphoblastic lymphoma/leukaemia(T-LBL/ALL). Methods Seventy-six cases of T-LBL/ALL were studied by using immunohistochemical EnVision method for PTEN. Fluorescence in-situ hybridization (FISH) for MLL gene (located on chromosome 11q23) was performed to detect its breakage and amplification. Results Among the 76 cases ofT- LBL/ALL, the positive rate of PTEN was 64.47 % (49/76), lower than that in reactivated lymphoid tissue (100 %, 20/20) (λ2= 19.220, P ＜0.05). PTEN expression was reversely correlated to theclinical stage, Ki-67 index and LDH level (P ＜0.05). Among the 76 cases, MLL gene with breakage of 11q23 was detected in 13 cases (17.11%), and amplification in 18 cases (23.68 %). Survival rate ot MLL gene breakage group was lower than that of non-breakage group (25.0 %, 43.6 %). Survival rate of MLL gene amplification group was lower than that of non-amplification group too (17.1%, 42.7 %). Both of breakage and amplification were related to prognosis ( λ 2 = 11.357, λ 2 = 4.533; P ＜0.05). Conclusion Anti-oncogene PTEN down-regulation may play an important role on the development and proceeding of T-LBL/ALL. MLL gene with breakage and amplification of 11q23 are helpful to predict prognosis of T-LBL/ALL. The case with MLL gene breakage and amplification of T-LBL/ALL may have a poor prognosis. It hints this group maybe a subtype of T-LBL/ALL.     

PTEN、MLL基因在T淋巴母细胞淋巴瘤/白血病的表达及其意义

Objective To investigate the significance and expression of PTEN, MLL in T lymphoblastic lymphoma/leukaemia(T-LBL/ALL). Methods Seventy-six cases of T-LBL/ALL were studied by using immunohistochemical EnVision method for PTEN. Fluorescence in-situ hybridization (FISH) for MLL gene (located on chromosome 11q23) was performed to detect its breakage and amplification. Results Among the 76 cases ofT- LBL/ALL, the positive rate of PTEN was 64.47 % (49/76), lower than that in reactivated lymphoid tissue (100 %, 20/20) (λ2= 19.220, P ＜0.05). PTEN expression was reversely correlated to theclinical stage, Ki-67 index and LDH level (P ＜0.05). Among the 76 cases, MLL gene with breakage of 11q23 was detected in 13 cases (17.11%), and amplification in 18 cases (23.68 %). Survival rate ot MLL gene breakage group was lower than that of non-breakage group (25.0 %, 43.6 %). Survival rate of MLL gene amplification group was lower than that of non-amplification group too (17.1%, 42.7 %). Both of breakage and amplification were related to prognosis ( λ 2 = 11.357, λ 2 = 4.533; P ＜0.05). Conclusion Anti-oncogene PTEN down-regulation may play an important role on the development and proceeding of T-LBL/ALL. MLL gene with breakage and amplification of 11q23 are helpful to predict prognosis of T-LBL/ALL. The case with MLL gene breakage and amplification of T-LBL/ALL may have a poor prognosis. It hints this group maybe a subtype of T-LBL/ALL.     

Suppression of EBNA1 expression inhibits growth of EBV-positive NK/T cell lymphoma cells

Extranodal nasal-type NK cell lymphoma (ENKL) is a high-grade malignancy and associated with EBV latent infection. An optimal therapy has not been discovery. Here, we investigated whether cell proliferation was inhibited by silencing Epstein-Barr virus nuclear antigen 1 (EBNA1) using RNA interference (RNAi) method in an EBV-positive ENKL cell line, HANK1 cells. We found that silencing EBNA1 expression by RNAi strategy inhibited cell growth and increased the expression of p27 protein and caused cell cycle arrest at G(1)-phase in HANK1 cells. In conclusions, low-level expression of p27 protein may partially attribute to latent EBV infection in ENKL. EBNA1 may be a good target for the treatment of EBV associated ENKL.     

异基因造血干细胞移植治疗急性T 淋巴细胞白血病和淋巴瘤：附50例临床报告

目的 探讨异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation,allo-HSCT）治疗急性T淋巴细胞白血病（T cell acute lymphoblastic leukemia,T-ALL）和急性T淋巴母细胞淋巴瘤（T cell acute lymphoblastic lymphoma, T-LBL）的疗效及预后。方法 回顾性分析2014—2019年于航天中心医院接受allo-HSCT的50例T-ALL/LBL患者的临床资料,分析其临床疗效、并发症及预后。结果 50例患者中男性41例,女性9例,中位年龄20.5岁（范围：9.0~63.0岁）;单倍体移植44例,脐血移植 2例,同胞全合移植 4例;T-ALL 40例,T-LBL 10例;移植前处于完全缓解（CR）状态16例,处于未完全缓解（非CR）状态34例。移植后,中位随访20个月（范围：1~84个月）,存活23例,死亡27例;移植后24个月的总生存率和无复发生存率分别为50.0%和44.0%,36个月的总生存率和无复发生存率分别为45.5%和40.0%。随访期间,共有20例患者复发,复发率为40.0%（20/50）。移植前获CR、无髓外病变、无中枢神经系统受累的患者预后较好,而移植前有无基因突变、不同预处理方案、有无急性/慢性GVHD患者的总生存期及无复发生存期组间比较差异无统计学意义（均P>0.05）。结论 在这项小样本、无对照的临床研究中,T-ALL/LBL患者在缓解期行allo-HSCT可能较挽救性移植的生存预后有所改善,其中复发为移植失败的主要原因。     

Rearrangement of human T cell receptor beta and gamma chain genes in adult T cell leukemia/lymphoma

We studied rearrangement of human T cell receptor genes (TCR) of C beta, C gamma, V gamma and J gamma in 34 cases of adult T cell leukemia/lymphoma (ATLL), consisting of 29 cases with monoclonally integrated HTLV-I proviral DNA (ATLL-W) and five without monoclonal integration (ATLL-O), in comparison with 12 cases of other peripheral T cell lymphomas (non-ATLL). All cases of both ATLL and non-ATLL showed some rearrangement of T cell receptor genes (TCRs) of C beta, C gamma, V gamma, or J gamma. Rearrangement of TCR beta was found in 28 of 29 cases of ATLL-W, all cases of ATLL-O, and eight of 12 cases of non-ATLL. Rearrangement of TCR gamma was observed in 21 of 22 cases of ATLL-W, and in all cases of ATLL-O and non-ATLL. In TCR gamma, rearrangement of C gamma was seen in six of 20 cases of ATLL-W, none of three ATLL-O cases and three of six cases of non-ATLL. V gamma rearrangement occurred in 14 of 18 cases of ATLL-W, one of two cases of ATLL-O, and three of six cases of non-ATLL. Rearrangement of J gamma was found in 16 of 22 cases of ATLL-W, two of five ATLL-O cases, and six of seven non-ATLL cases. Rearrangement was more frequent in ATLL-W than in ATLL-O and non-ATLL. The incidence rate of rearrangement of V gamma families of V gamma 1, V gamma 2, and V gamma 3 was nearly the same in each group, except for deletion of V gamma 3, which was often observed in ATLL but was absent in non-ATLL. These results indicate the usefulness of detection of TCR and HTLV-I proviral DNA to differentiate ATLL from other T cell malignancies.     

Topoisomerase IIalpha expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome.

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3-4 years. Treatment usually consists of combination chemotherapy, often including topoisomerase (topo) inhibitors such as doxorubicin, etoposide and mitoxantrone. Topo IIalpha is an enzyme that is needed whenever uncoiling of DNA is necessary during the cell cycle. The enzyme is a marker of cell proliferation. We analyzed the expression of topo IIalpha in relation to Ki-67 and the clinical outcome in patients with MCL. Biopsy specimens from 95 untreated patients enrolled in two multicenter trials (1975-1985) were investigated immunohistochemically with monoclonal antibodies against topo IIalpha (Ki-S4) and Ki-67 (Ki-S5). Patients with low (0-10%) topo IIalpha expression had a median overall survival time of 49.0 months, compared to 17.0 months for patients with high (more than 10%) topo IIalpha expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time related to the percentage of topo IIalpha (P<0.001) and Ki-67 (P<0.001) positive tumor cells. Multivariate Cox regression analysis revealed the expression of topo IIalpha as the most important prognostic factor (P<0.001) in MCL superior to the international prognostic index (IPI), the Ki-67 index and other clinical characteristics.     

Adhesion molecule expression, clinical features and therapy outcome in childhood acute lymphoblastic leukemia.

In view of the relevance of adhesion molecule expression for the mechanisms of homing, trafficking and spreading of malignant cells, we have investigated the expression of surface adhesion molecules in lymphoblasts from 57 acute lymphoblastic leukemia (ALL) cases and tried to correlate the adhesive phenotype with immunological typing, prognostic factors at diagnosis and clinical follow-up. Blasts from all cases expressed adhesion molecules at high rates. Beta1 integrin chain (CD18) was consistently found on blasts from most ALL cases: among integrins of the beta2 family. LFA-1 was detected in 58% of cases, in the virtual absence of other alpha chains. CD54 and CD58 were expressed in variable proportions by ALL blasts and CD44 was detected in the majority of the malignant cells, whereas the CD62L selectin was only present in 24% of cases. B-lineage ALL's displayed similar adhesion molecule phenotypes irrespective of maturational stages of the leukemic cells. We found a significantly reduced expression of beta2 alphaL integrins in the hybrid ALL cases (CD13 and/or CD33 positive). However, these cases did not show differences in clinical presentation and behaviour in comparison with patients of other groups. We did not find a significant correlation between adhesion molecule expression and well established risk factors (age, white blood cell count, central nervous system involvement, chromosomal abnormalities), with the exception of splenomegaly, that was significantly associated with CD18 expression. In the follow-up, no evidence of significant correlation between adhesive phenotype and adverse events such as leukemic relapse and death was found. In conclusion, although expression of adhesion molecules on lymphoblasts confirms the phenotypic heterogeneity of ALL, it appears that this is not relevant for the clinical aspects of the disease and for prognosis.     

PCR-SSCP检测非霍奇金淋巴瘤患者骨髓克隆性T细胞受体基因重排及其临床意义

背景与目的：进一步了解非霍奇金淋巴瘤（non-Hodgkin‘s lymphoma,NHL)患者骨髓标本克隆T细胞受体（T cell receptor,TCR)基因重排情况及临床意义。方法：应用聚合酶链反应（polymerase chain reaction,PCR)联合单链构象多态性（single-strand conformation polymorphism,SSCP),分析43例NHL患者骨髓标本TCRVγI-Jγ基因重排情况。结果：43例NHL患者有26例（60．5％）存在克隆性TCRVγI－Jγ基因重排。16例骨髓形态学检查未发现淋巴瘤细胞浸润者中有3例（18．8％）发现克隆性TCRVγ－Jγ基因重排。此3例患者分别于4－9个月后行骨髓形态检查时发现淋巴瘤细胞浸润。27例骨髓形态学检查有淋巴瘤细胞浸润者有23例（85．2％）存在克隆性TCRVγI－Jγ基因重排阳性,26例PCR扩增阳性病例经SSCP分析发现7例（26．9）％存在寡／亚克隆重排。7例存在寡／亚克隆重排患者经3－11个月有5例（71．4％）发展为白血病,存在寡／亚克隆重排NHL患者1年内转化为白血病的发生率显著高于无寡／亚克隆重排患者（10．5％）（P＜0．005）。结论：应用PCR检测NHL患者骨髓标本克隆性TCRVγ－Jγ基因重排可较骨髓形态学检查更早发现NHL患者骨髓浸润微小病灶。具有寡／亚克隆NHL患者更易发展为白血病,还可发展为急性非淋巴细胞白血病。     

Leu M-1 antigen: comparative expression in Hodgkin's disease and T cell lymphoma

Expression of the granulocyte antigen Leu M-1 is characteristic of Reed-Sternberg cells and the related mononuclear cells of Hodgkin's Disease. Leu M-1 has been proposed as a specific immunological marker for Hodgkin's Disease which may be otherwise difficult to distinguish both morphologically and immunologically from non Hodgkin's lymphomas of peripheral T-cell type. In the present study the comparative expression of Leu M-1 in Hodgkin's Disease and peripheral T cell lymphoma was studied in a series of 43 cases including 25 cases of Hodgkin's Disease and 18 cases of immunologically documented peripheral T cell lymphoma. Leu M-1 staining by avidin-biotin-peroxidase complex technique in acetone fixed frozen sections was observed in 22 of 25 cases of Hodgkin's Diseases, (2 of 3 cases of lymphocyte predominant Hodgkin's Disease and 1 case of mixed cellularity were negative) and in 4 of 18 cases of peripheral T cell lymphoma. The pattern of staining in the peripheral T cell lymphomas was indistinguishable from that observed in Hodgkin's Disease in 2 of the cases. Leu M-1 staining appears to be of limited diagnostic value in the differential diagnosis of Hodgkin's Disease and T cell lymphoma. Absence of Leu M-1 staining in frozen tissue however, makes a diagnosis of Hodgkin's Disease (with the exception of the lymphocyte predominant form) unlikely.     

MAGE-C1/CT-7 expression in plasma cell myeloma: sub-cellular localization impacts on clinical outcome

Plasma cell myelomas (PMs) have a poor prognosis. Cancer-testis (CT) antigens are immunogenic proteins, representing potential targets for tumor vaccination strategies. The expression of the CT antigens GAGE, MAGE-A4, MAGE-C1/CT-7, and NY-ESO-1 was investigated on paraffin-embedded bone marrow biopsies from 219 PM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients. The frequency and prognostic impact of these CT antigens were compared with known morphological prognostic markers (i.e. Mib1 labeling index) and the presence of the translocations t(4;14)(p16.3; q32) and t(11;14)(q13;q32). We show that MAGE-C1/CT-7 is the most prevalent CT antigen, expressed in 57% of PMs in a high percentage of tumor cells. While MAGE-C1/CT-7 was absent in non-malignant plasma cells, plasma cells of patients with MGUS did express MAGE-C1/CT-7, but no other CT antigens. MAGE-C1/CT-7 was more frequently expressed in PMs with an elevated proliferation rate (Mib1 >10%) compared to PMs with a low proliferation rate (Mib1 ≤10%, 71% versus 29%, P  < 0.001) and correlated with overall survival, depending on its subcellular distribution. PMs with pure cytoplasmic MAGE-C1/CT-7 expression showed a better prognosis (48 months versus 33 months, P  < 0.05) than PMs with combined nuclear-cytoplasmic or nuclear expression only. Thus, expression of MAGE-C1/CT-7 in patients with monoclonal gammopathies represents a predictor of outcome and overt malignant transformation. ( Cancer Sci 2008; 99: 720–725)     

71例鼻腔NK/T细胞淋巴瘤放化疗效和预后因素分析

目的回顾性分析71例鼻腔NK／T细胞淋巴瘤患者的放化疗疗效和预后因素。方法12年余间安徽省立医院肿瘤放疗科共收治原发鼻腔NK／T细胞淋巴瘤71例，其中男40例，女31例，年龄15—80岁，中位年龄44岁。AnnArbor分期ⅠE、ⅡE、ⅢE、ⅣE期分别为51、13、1、6例。单纯放疗23例，余48例放化疗。采用Kaplan-Meier法行生存分析，单因素分析用Logrank法，多因素分析用Cox比例风险模型。结果全组死亡33例，5年总生存率为48．2％。ⅠE、ⅡE、ⅢE＋ⅣE期患者5年总生存率分别为59．O％、35．8％、0％（χ^2=42．61，P〈0．01）。单纯放疗组和放化疗组5年总生存率分别为57．9％和61．5％（χ^2=10．99，P〉0．05）。多因素回归分析表明治疗前行为状况（Ps）评分、初诊时病灶超腔、近期疗效是独立预后因素。结论放疗加CHOP方案为主的化疗未提高ⅠE＋ⅡE期患者远期生存率。治疗前PS评分、初诊时病灶超腔、近期疗效可作为判断鼻腔NK／T细胞淋巴瘤临床预后的参考指标。     

Association between syndecan-1 expression and clinical outcome in squamous cell carcinoma of the head and neck.

Syndecans are a family of cell-surface heparan sulphate proteoglycans which are involved in cell-matrix interactions and growth factor binding. Syndecan-1 binds basic fibroblast growth factor (bFGF) and several components of the extracellular matrix. Syndecan-1 expression is induced during keratinocyte differentiation and reduced during the formation of squamous cell carcinomas (SCCs). The purpose of this study was to examine the association of syndecan-1 expression with prognostic factors and clinical outcome in SCC of the head and neck. Frozen sections of 29 primary SCCs were analysed for syndecan-1 expression using immunohistochemical methods. Intermediate or strong staining for syndecan-1 was associated with a smaller primary tumour size (P = 0.0005) and higher histological grade of differentiation (P = 0.006) than negative or weakly positive staining. In a univariate analysis, syndecan-1-positive tumours were associated with higher overall (P = 0.001) and recurrence-free survival (P = 0.003) than those tumours with no or little syndecan-1 expression. The results suggest that syndecan-1 could be an important prognostic factor of SCC of the head and neck. Further studies on the prognostic significance of syndecan-1 expression in SCCs are warranted.     

The outcome and characteristics of patients with relapsed adult T cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation

Treatment options for patients with adult T cell leukemia/lymphoma (ATLL) who have relapsed disease after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) are limited. To clarify which patients with ATLL are likely to benefit from these treatment options and to define patient populations for novel treatments, we performed a nationwide retrospective analysis of 252 Japanese patients who had relapsed ATLL after allo‐HSCT. Some long‐term survivors remained after tapering and withdrawal of immunosuppressive agents. Thirty‐six patients who received donor lymphocyte infusion had a better overall survival (OS) in comparison to those who did not [hazard ratio (HR), 0.63; 95% confidence interval (CI), 0.43‐0.93; P = .02], suggesting the efficacy of a graft‐versus‐ATLL (GvATLL) effect even after relapse. Multivariate analysis demonstrated that skin lesions at initial relapse of ATLL were independently associated with higher OS (HR, 0.41; 95% CI, 0.22‐0.74; P = .003), indicating that the skin is a susceptible target organ of GvATLL. This study suggested that enhancement of a GvATLL effect is a potential therapeutic option for relapsed disease after allo‐HSCT. Further investigations of incorporation of immune‐based approaches with new molecular target drugs into the therapeutic options of patients with ATLL before and after transplantation are warranted.