急性髓系白血病患者HOX11基因的表达及意义

目的 探讨HOX11基因在急性髓系白血病(acute myeloid leukemia,AML)中的表达及对预后的影响,为个体化治疗提供依据.方法 应用多重巢式RT-PCR方法对73例初诊AML患者的融合基因进行检测,对HOX11基因表达阳性和阴性的患者进行标准治疗后的疗效进行分析.结果 在预后良好组、预后中等组及预后不良组AML患者的标准治疗中,HOX11基因阳性表达患者的第一疗程完全缓解率(complete remission rate)并不高于阴性表达的患者(P＞0.05),而复发或死亡率(relapse or mortality rate)与HOX11基因阴性表达的患者比较差异有统计学意义(P＜0.05).结论 HOX11基因的表达可能影响AML患者的预后.     

NOTCH1对T-ALL抑癌基因ID4的负调控作用

目的 研究DNA结合抑制因子4（inhibitor of DNA binding 4, ID4）在急性T淋巴细胞白血病（T-cell acute lymphoblastic leukemia, T-ALL）中的表达水平,探讨NOTCH1与ID4的相关性及其调控机制。方法 通过Oncomine和Pieters R数据库分析T-ALL患者与正常捐献者中ID4的表达差异及T-ALL患者中NOTCH1与ID4的相关性,用qRT-PCR和Western blot检测阻断NOTCH1或激活NOTCH1后ID4的表达变化进行验证。用生物信息学的方法特异预测出microRNA-342（miR-342）靶向ID4,通过双荧光素酶报告体系进行验证。过表达或沉默miR-342后,qRT-PCR和Western blot检测ID4的表达变化。阻断NOTCH1或激活NOTCH1,qRT-PCR检测miR-342的表达变化。结果 ID4在T-ALL患者中的表达较正常组显著下调（P＜0.01）;ID4受NOTCH1负调控（P＜0.05）;双荧光素酶报告系统验证预测结果正确;过表达miR-342后,ID4的表达受到显著抑制（P＜0.05）,沉默miR-342后,ID4的表达明显上调（P＜0.05）;NOTCH1信号的阻断能够抑制miR-342的表达,NOTCH1信号的激活能够上调miR-342的表达。结论 NOTCH1通过激活miR-342对ID4的负调控作用从而下调抑癌基因ID4的表达,促进T-ALL的发生。     

T-Cell Acute Lymphoblastic Leukemia with t(11;14) in Children

We review and update our examination of the clinical and biologic findings in 19 cases of acute lymphoblastic leukemia (ALL) with the t(11;14) and discuss the literature relevant to the clinical, biologic, and molecular aspects of these translocations. In nine consecutively diagnosed cases at St. Jude Children's Research Hospital and 10 cases reported by other institutions, clinical features did not differ among T-cell ALL patients with and without the t(11;14), although leukemic cells with this translocation were more likely to coexpress CD4 and CD8 antigens. The t(11;14)(p13;q11) appears to occur exclusively in T-cell malignancies of intermediate- or late-stage thymocyte differentiation; further studies will be needed to determine whether it has prognostic significance.     

Therapeutic Targeting of c-Myc in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

T-ALL patients treated with intensive chemotherapy achieve high rates of remission. However, frequent long-term toxicities and relapses into chemotherapy-refractory tumors constitute major clinical challenges which could be met by targeted therapies. c-MYC is a central oncogene in T-ALL, prompting the exploration of the efficacy of MYC inhibitors such as JQ1 (BET-bromodomain inhibitor), and SAHA (HDAC inhibitor). Using a standardized ex vivo drug screening assay, we show here that JQ1 and SAHA show competitive efficiency compared to inhibitors of proteasome, PI3K/AKT/mTOR and NOTCH pathways, and synergize in combination with Vincristine. We also compared for the first time the in vivo relevance of such associations in mice xenografted with human primary T-ALLs. Our data indicate that although treatments combining JQ1 or SAHA with chemotherapeutic regimens might represent promising developments in T-ALL, combinations will need to be tailored to specific subgroups of responsive patients, the profiles of which still remain to be precisely defined.     

Oligoclonal Immunoglobulin Gene Rearrangements in Philadelphia Chromosome-positive Common Acute Lymphoblastic Leukemia

The occurrence of more than two rearranged bands of immunoglobulin heavy chain (IgH) genes in B precursor acute lymphoblastic leukemia (ALL) has recently been documented. To elucidate the nature of such leukemias, we studied 30 patients with common ALL, including 6 patients with Philadelphia chromosome (Ph¹)-positive ALL, by immunophenotyping and genotyping. In 10 of the 30, Southern blotting showed oligoclonal patterns of IgH gene arrangements, which were frequently detected in Ph¹-positive ALL. In one patient of the 10, three rearranged bands of Ig k chain genes were detected. Ph¹ abnormality and co-expression of myeloid associated antigens were found in 5 and 5 of the 10, respectively. Detection of multiple fragments of IgH genes would be suggestive of multipotent progenitor origin of these ALL.     

Molecular Diagnosis of the Philadelphia Chromosome in Acute Lymphoblastic Leukemia

The Philadelphia (Ph¹) chromosome was the first specific chromosomal abnormality to be consistently associated with a particular neoplasm, in this case chronic myelogenous leukemia (CML,)¹. Formed by a reciprocal translocation between chromosomes 9 and 22², the 22q-, or Ph¹ chromosome is found in the malignant cells of more than 90% of patients with CML³. The presence of the molecular equivalent of a Ph¹ chromosome is such a consistent finding in CML that it IS now the basis of a diagnostic test in routine clinical use.     

Variant and Masked Translocations in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is characterized by a unique hemorrhagic syndrome, disseminated intravascular coagulation, and the association with the specific (15; 17)(q22-23;q 12-21) translocation, which disrupts the retinoic acid receptor alpha (RARA) and the promyelocytic leukemia (PML) genes. The t(15; 17) leads to the formation of two reciprocal fusion genes, PMURARA on chromosome 15 and RARA/PML on chromosome 17; it is responsible for the unique response of the disease to retinoic acid (ATRA) treatment. As was described for chronic myeloid leukemia and its associated t(9;22) [Philadelphia chromosome], variant translocations have been reported in APL, which are either complex translocations involving additional chromosome(s), or simple variant translocations involving only either one chromosome 15 or 17 and any of several chromosomes. Rearrangements of RARA and PML were documented in some of these variant translocations. In contrast, recent molecular analysis of APL cases with cytogenetically normal chromosomes 15 and 17 revealed the occurrence of submicroscopic translocations, leading to the formation of non reciprocal fusion genes, either PMURARA or RARA/PML only. Detailed analysis of such cases may shed light on the mechanisms of translocation, on the selection of oncogenic products, and on the respective role(s) of the products of the translocation. Demonstration of the existence, in some APL-like leukemias, of masked translocations with involvement of PML and RARA, thus allows to (i) confirm the diagnosis of APL, (ii) adapt the treatment and (iii) monitor the residual disease. Finally APL-like leukemias were recently reported, with either a t(11; 17) or t(5; 17), resulting in the fusion ofRARA to genes other than PML; these patients do not appear to respond to ATRA treatment. Altogether, these results emphasize the usefulness of a molecular definition of APL.     

MTRR基因A66G多态性与儿童急性淋巴细胞白血病关系的Meta分析

目的 评估甲硫氨酸合成酶还原酶（MTRR）基因A66G多态性与儿童急性淋巴细胞白血病（ALL）发生风险的关系。方法 全面检索PubMed、Elsevier、Embase、中文期刊全文数据库（CNKI）和万方数据库,收集探索MTRR基因A66G多态性与儿童ALL发生关系的病例对照研究,纳入符合入选标准的文献并评估其质量。优势比（ORs）及95%可信区间（CIs）评估关联强度。应用RevMan 5.2软件对纳入研究进行异质性检验和效应值合并,漏斗图评估发表性偏倚,敏感性分析采用逐一排除的方法以评估结果的稳定性。结果 共纳入7篇文献,包括儿童ALL患者2 326例,对照3 090例。异质性检验结果表明纳入研究间无显著异质性,采用固定效应模型合并数据。Meta分析结果示,在整体人群纯合子模型和显性模型发现MTRR A66G多态性与儿童ALL风险有关联（GG vs. AA: OR=0.81, 95%CI: 0.69~0.95, P=0.009; AG+GG vs. AA: OR=0.87, 95%CI: 0.77~0.98, P=0.03）;根据种族 进行亚组分析时在白种人群中发现显著性关联（AG vs. AA: OR=0.84, 95%CI: 0.72~0.99, P=0.04; GG vs. AA: OR=0.79, 95%CI: 0.66~0.95, P=0.01; AG+GG vs. AA: OR=0.82, 95%CI: 0.71~0.96, P=0.01）。漏斗图未检测出显著性发表性偏倚,敏感性分析表明结果稳定可靠。结论 目前Meta分析表明MTRR基因A66G多态性与儿童ALL发生风险存在关联,尤其在白种人群。     

重组白介素11联合HAM方案治疗急性髓性白血病

[目的]研究重组白介素11(rhIL-11)联合HAM方案化疗对急性髓性白血病的疗效.[方法]将急性髓性白血病患者分成3组,一组行HAM(三尖杉酯碱、阿糖胞苷、米托蒽醌)方案化疗2个疗程,一组行DA(柔红霉素、阿糖胞苷)方案化疗2个疗程,一组在HAM方案化疗的基础上加用rhIL-11治疗2个疗程,观察血象三系细胞的动态变化、血象最低值及恢复时间;观察骨髓幼稚细胞的比例,判定疗效(完全缓解、部分缓解及未缓解);观察各组出血情况及所需输注血小板的患者比例.[结果]HAM化疗组疗效优于DA化疗组;重组白介素11组与另两组比较,血象恢复更快;血小板最低值更高;出血发生率更低;所需输注血小板的患者比例更少;rhIL-11组疗效与单用HAM方案化疗的疗效相仿.[结论]rhIL-11联合HAM方案化疗能有效治疗急性髓性白血病,rhIL-11的主要作用是升高血小板.     

Implication of Dynamin-2 (DNM2) Mutations in Adult T-cell Acute Lymphoblastic Leukemia

Background:The objective of the present study was to improve the risk stratification of T-cell Acute Lymphoblastic Leukemia (T-ALL) patients. It aimed to identify the frequency and clinical impact of DNM2 gene mutations among adult T-ALL cases. Methods: The current study included 25 T-ALL patients before starting their treatment. Mutational analysis of DNM2 gene (exons 18 and 22) was performed for all patients using Macrogen 3730 apparatus. Results: We identified DNM2 gene mutations in 19 out of 25 (76%) patients. The detected mutations were either missense or deletion. Only active mutations (deletion) were associated with poor induction remission response and high frequency of relapse. Two novel mutations were addressed among the studied cohort of patients. They included c.1866G>C (p.V596L) and c.1872delA in exon 18. A high frequency of silent mutations was also found in T-ALL patients, but with no impact on clinical features. Conclusion: The DNM2 mutations were prevalent among adult T-ALL patients and might have a role in the pathogenesis of the disease. Active DNM2 mutations were associated with poor clinical outcome. Moreover, high frequency of DNM2 mutations indicated that these mutations could be utilized in detection of minimal residual disease in T-ALL patients.     

Multidrug Resistance (MDR) Gene Expression in Acute Non Lymphoblastic Leukemia: Sequential Analysis

Sequential evaluation of P-glycoprotein expression was performed in 29 patients with acute nonlymphoblastic leukemia using immunocytochemistry with the C219 antibody. At diagnosis, 32% of the patients exhibited more than 5% of the P-gp(+) leukemic cells. Under chemotherapy, 62% of the patients eventually expressed a subset of P-gp positive leukemic cells. After conventional doses of cytosine-arabinoside (Ara-C) and daunorubicin or mitoxantrone, positive P-gp cells were noted in 65% of the cases. This percentage was significantly higher (p = 0.002) than the proportion of positive cases (15%) observed after regimens containing either intermediate doses of Ara-C or cyclosporine A, a P-gp modulator.     

Acute Complications and Survival Analysis of Childhood Acute Lymphoblastic Leukemia: A 15-year Experience

BackgroundWe evaluated the acute complications that occurred during the treatment of childhood acute lymphoblastic leukemia (ALL) and documented the survival rates of children with ALL.Materials and MethodsWe retrospectively evaluated 110 children with a diagnosis of ALL treated with the Children’s Oncology Group protocol from 1999 to 2014. The demographic, clinical, and laboratory data of 110 patients and acute complications of eligible and evaluable 105 patients were recorded.ResultsOf the 110 patients, 65 were male and 45 were female. The mean age at admission was 8.3 ± 5.2 years. Ninety-seven patients (88.2%) had been diagnosed with pre–B-cell ALL, 11 (10%) with T-cell ALL, 1 (0.9%) with mixed phenotype acute leukemia, and 1 (0.9%) with mature B-cell acute leukemia. Of the 110 patients, 40 (36.3%) were in the standard-risk group and 70 (63.7%) were in high-risk group. Of the 110 patients, 105 had been followed up regularly and evaluated for acute complications. Infection was the most common complication (n = 93; 88.5%), followed by gastrointestinal (n = 29; 27.6%), neurologic (n = 28; 26.6%), metabolic/endocrine (n = 16; 15.2%), drug-related hypersensitivity (n = 16; 15.2%), avascular necrosis (n = 13; 12.3%), thrombotic (n = 11; 10.4%), severe psychiatric (n = 2; 1.9%), and various other (n = 12; 11.4%) complications. Of the 110 patients, 98 were assessed in terms of survival analysis. The 5- and 10-year overall survival rates were both 85.9% (standard error [SE], 3.6%). The relapse-free survival rates at 1, 3, and 5 years were 97.9% (SE, 1.5%), 91.3% (SE, 3%), and 86.3% (SE, 3.7%), respectively.ConclusionChildhood ALL, although categorized as curable malignancy owing to the improvements in treatment strategies in recent years, can cause acute complications affecting various systems. Thus, patients should be treated and followed up by multidisciplinary medical teams with high expertise.     

Comparison of Risk Grouping Methods for Acute Lymphoblastic Leukemia in Children

Four criteria for the risk grouping of children's acute lymphoblasticleukemia: Children's Cancer and Leukemia Study Group (CCLSG)in Japan, Southwest Oncology Group (SWOG) and Children's CancerStudy Group (CCG-141) in the USA, Berlin-Frankfurt-Munster StudyGroup (BFM) in West Germany, were applied retrospectively to109 patients with the disease who had been treated randomlyin Sapporo National Hospital from 1978 to 1986. No significantdifference in respect of survival curve was found in most combinationsbetween low-and intermediate-risk groups, nor among either low-or intermediate-risk groups (P>0.10, Cox-Mantel's test).Among the four high-risk groups formed by the application ofthese criteria, no significant difference was noted (P>0.10),but there were significant differences between the high-riskand the low- or intermediate-risk groups (P<0.05 or 0.10).With such results, a comparison of therapeutic results in high-riskgroups yielded by different study groups would appear to benot only possible but useful, for example, in improving therapeuticmethods.