EVI1基因阳性的急性髓系白血病发病机制及潜在治疗靶点的研究进展

原癌基因EVI1在急性髓系白血病(AML)的发病中起到了重要作用,EVI1基因阳性的AML通常伴有EVI1异常高表达,患者预后不良。目前已经对EVI1阳性的AML的发病机制展开了研究,发现EVI1编码的锌指蛋白可以结合多种DNA,并且EVI1和AML细胞的凋亡、分化、增殖、化疗耐药等密切相关。此外,随着二代测序技术的普遍应用,发现了一系列EVI1阳性的AML相关的共突变和下游靶点。文章阐述了EVI1基因导致AML发病的机制和潜在的治疗靶点。     

有助于t(8;21)急性髓细胞白血病的诊断和预后判断的免疫表型特征

 t(8;21)核型急性髓细胞白血病（AML）是临床常见类型白血病,更多见于FAB分型M2型。由于21号染色体上的AML1基因和8号染色体上的ETO基因发生融合,而产生AML1-ETO融合蛋白。t(8;21) AML具有独特的免疫表型,这些独特的免疫表型特征不仅有助于t(8;21) AML的诊断,而且决定了t(8;21) AML的预后     

2011年美国血液学会年会急性髓系白血病临床研究的最新进展

 急性髓细胞白血病（AML）是每年美国血液学会（ASH）年会的最主要的组成部分。第53届ASH会议共有887篇有关AML的论文,其中不少涉及AML的临床研究方面,就AML治疗方案的优化、老年AML的治疗及AML的靶向治疗等方面的亮点进行介绍。     

急性髓系白血病细胞粘附分子的表达及意义

多种粘附分子在急性髓系白血病(AML)细胞上的表达与AML发生、发展及转归相关,对指导AML的治疗,监测AML的发展及预后有一定意义.本文将此方面的相关文献进行综述,以探讨AML细胞粘附分子表达的临床意义.     

难治性急性髓系白血病(M2a)的基因表达谱

背景与目的:复发是急性髓系白血病(acutemyeloidleukemia,AML)治疗失败的主要原因,部分AML复发时其免疫表型和细胞遗传学已发生了改变。耐药是AML难治的主要原因,AML耐药与基因的异常表达有关,目前对AML复发/难治或耐药相关基因及其表达所知甚少。本研究检测AML初诊与复发/难治之间的基因表达差异,为阐明AML复发/难治的可能机制提供依据。方法:应用基因芯片技术,对5例自身配对初诊与复发/难治AML鄄M2a患者之间骨髓单个核细胞的基因表达差异进行了检测。结果:在检测的925个基因中,14个基因在初诊与复发/难治AML鄄M2a之间差异表达,其中12个基因(涉及细胞信号转导、DNA复制、转录调节和RNA加工以及细胞循环等相关基因)在复发时明显上调,参与DNA复制过程的RRM1基因上调最显著。结论:在AML鄄M2a复发/难治的发生过程中有多个基因共同参与,这些基因的高表达提示复发/难治AML细胞增殖能力可能更强。     

急性髓系白血病的免疫治疗:有多少成果可以转化临床?

急性髓系白血病(AML)是一种高度异质性的恶性血液病,复发率较高.近年来免疫治疗在AML中取得了一定的疗效,异基因造血干细胞移植、过继性免疫治疗、单克隆抗体和疫苗治疗可使相当一部分AML患者获得长期生存,但仍不能满足所有患者的治疗需要.AML的免疫治疗有相当大的发展潜力,期待各种免疫治疗手段能在充分发挥自身优势、减少不良反应的情况下,更好地改善AML的疗效.     

淋系抗原表达对急性髓系白血病预后的价值

目的:探讨淋系抗原表达在急性髓系白血病（acute myeloid leukemia,AML）预后方面的临床意义。方法:应用流式细胞术检测我院101例初诊AML患者的免疫表型,以CD7-CD19-CD56-AML为对照组,将CD7+AML组、CD19+AML、CD56+AML组与对照组的临床特征、疗效进行分析比较,随访并观察生存曲线的差异。结果:101例AML患者中淋系抗原表达者52例(51.5%),CD7抗原表达29例（28.7%）,CD56抗原表达29例（28.7%）,CD19抗原表达13例（12.8%）;CD7+AML、CD19+AML、CD56+AML患者与对照组间的发病年龄、肝脾大、髓外浸润、白细胞计数、血红蛋白、骨髓原始细胞比例差异无统计学意义（P＞0.05）,CD7+AML组血小板计数偏低（P＜0.05）;CD56+AML组首次完全缓解率（CR）率及总CR率均低于对照组（P＜0.05）;CD7+AML、CD19+AML组首次CR率及总CR率与对照组相比差异均无统计学意义（P＞0.05）;与对照组相比,CD56+AML组无复发生存期（RFS）缩短（P＜0.05）,CD7+AML、CD19+AML组RFS与对照组差异无统计学意义（P＞0.05）。结论:CD56+AML患者常规化疗不敏感,疗效差,CD56抗原可能是AML患者的预后不良因素;CD7、CD19抗原不影响AML患者的预后。     

骨髓基质细胞通过TSP-1/CD36通路对急性髓系白血病细胞影响的初步研究

目的：探讨骨髓基质细胞（bone marrow-derived mesenchymal stromal cells,BM-MSCs）对急性髓系白血病（acute myeloid leukemia,AML）细胞影响的作用机制。方法：构建MLL-AF9过表达诱导的AML小鼠模型,通过PCR比较AML小鼠和野生型小鼠（WT）BM-MSCs内TSP-1的表达差异。通过慢病毒载体使AML小鼠来源的BM-MSCs高表达TSP-1后,与AML细胞行transwell共培养,检测AML细胞表面TSP-1受体CD36及CD47的表达及AML细胞的生长情况。在共培养体系中加入CD36抑制剂N-油酰基硫代琥珀酰亚胺,检测AML细胞增殖、凋亡的变化。结果：AML小鼠BM-MSCs中TSP-1的表达低于对照组。过表达TSP-1的BM-MSCs与AML细胞行transwell共培养后AML细胞的生长受到抑制,且AML细胞表面的CD36受体表达升高,但CD47表达无明显差异。在共培养体系中加入CD36抑制剂N-油酰基硫代琥珀酰亚胺后,AML细胞增殖加快,凋亡减少。结论：TSP-1/CD36信号通路有望成为治疗AML...     

急性髓性白血病与难治性髓性白血病患者血浆tPA及PAI活性变化的临床意义

我所1995年1月—2000年12月对住院初治急性髓性白血病(AML)、治疗后缓解期的AML、难治性AML、缓解期难治性AML患者血浆作了tPA及PAI活性的检测，并与正常人作对照，现总结分析如下。……     

AML/TMDS与MDS-AML的对比研究

目的 :分析三系病态造血的急性髓系白血病 (AML/TMDS)与骨髓增生异常综合征演变为急性髓系白血病 (MDS AML)的差异。方法 :采用常规形态学和细胞化学染色方法观察患者外周血和骨髓细胞。结果 :AML/TMDS患者血小板计数和外周原始细胞百分率高于MDS AML(P <0 0 5 ,P <0 0 1) ;小巨核细胞和Pseudo pelger异常明显低于MDS AML(P <0 0 5 ,P <0 0 1) ,2组病例MPO染色阳性率基本一致 ,但AML/TMDS患者MPO积分显著高于MDS AML(P <0 0 1)。AML/TMDS患者多核原始红细胞明显低于MDS AML(P <0 0 5 ) ;AML/TMDS与MDS AML患者巨大血小板分别为 2 3 1%和 86 7%。结论 :AML/TMDS与MDS AML白血病克隆不同 ,正确诊断对确定方案、判断疗效及预后有重要意义     

Genetic alteration patterns and clinical outcomes of elderly and secondary acute myeloid leukemia

To illustrate the clinical and genetic features of elderly and secondary acute myeloid leukemia (AML) patients, we compared 145 elderly AML (e‐AML) and 55 secondary AML (s‐AML) patients with 451 young de novo AML patients. Both e‐AML and s‐AML patients showed lower white blood cell (WBC) and bone marrow (BM) blasts at diagnosis. NPM1, DNMT3A, and IDH2 mutations were more common while biallelic CEBPA and IDH1 mutations were less seen in e‐AML patients. s‐AML patients carried a higher frequency of KMT2A‐AF9. In treatment response and survival, e/s‐AML conferred a lower complete remission (CR) rate and shorter duration of event‐free survival (EFS) and overall survival (OS) compared with young patients. In multivariate analysis, s‐AML was an independent risk factor for OS but not EFS in the whole cohort. Importantly, intensive therapy tended to improve the survival of e/s‐AML patients without increasing the risk of early death, and hematopoietic stem cell transplantation (HSCT) could rescue the prognosis of s‐AML, which should be recommended for the treatment of fit patients.     

LFA-1与ICAM-1在急性髓性高白细胞白血病中的表达

 目的 研究高白细胞急性髓性白血病（AML）患者白血病细胞与内皮细胞的黏附状况以及LFA-1和ICAM-1在高白细胞AML中的表达,探讨AML患者高白细胞的发生机制。方法 观察高白细胞AML患者白血病细胞与内皮细胞的黏附作用;检测高白细胞AML骨髓单个核细胞（BMMNC）培养上清对正常白细胞与内皮细胞黏附的影响;流式细胞仪检测高白细胞AML患者BMMNC表面LFA-1的表达以及高白细胞AML患者BMMNC培养上清作用24 h后内皮细胞ICAM-1的表达。结果 与非高白细胞AML组相比,高白细胞AML患者白血病细胞与内皮细胞的黏附率明显增加;BMMNC表面LFA-1的表达显著增加; BMMNC培养上清作用后内皮细胞ICAM-1的表达明显增高及与正常白细胞黏附明显增加。结论 高白细胞AML细胞分泌较多的LFA-1,同时刺激内皮细胞分泌ICAM-1增加,促使白血病细胞与内皮的黏附增加,增高的LFA-1与ICAM-1共同作用可能在高白细胞白血病的发生中起一定作用     

Metachronous and synchronous presentation of acute myeloid leukemia and lung cancer

Smoking is associated with both acute myeloid leukemia (AML) and lung cancer. We therefore searched our database for concomitant presentation of AML and lung cancer. Among 775 AML cases and 5225 lung cancer cases presenting to Roswell Park Cancer Institute between the years January 1992 and May 2008 we found 12 (1.5% of AML cases; 0.23% of lung cancer cases) cases (seven metachronous and five synchronous) with AML and lung cancer. All but one patient were smokers. There were no unique characteristic of either AML or lung cancer in these patients. Nine patients succumbed to AML, one died from an unrelated cause while undergoing treatment for AML, one died of lung cancer and one patient is alive after allogeneic transplantation for AML. In summary, this study supports the need for effective smoking cessation programs.     

Comparison between pediatric acute myeloid leukemia (AML) and adult AML in VEGF and KDR (VEGF-R2) protein levels

We reported previously that high levels of vascular endothelial growth factor (VEGF) were associated with shorter survival in adult acute myeloid leukemia (AML) patients. In this study, cellular VEGF and its receptor, VEGF-R2 (kinase domain receptor (KDR)), were analyzed in 45 pediatric AML patients using Western blot and solid-phase radioimmunoassay (RIA). Cellular VEGF levels were significantly lower in pediatric AML compared to adult AML patients. In contrast, there was no significant difference in VEGF-R2 levels between adult and pediatric AML. Higher VEGF and VEGF-R2 levels in pediatric AML patients correlated with higher white blood cell (WBC). Unlike in adults, VEGF and VEGF-R2 levels in pediatric AML patients did not correlate with survival. This data suggest that the role of VEGF and its receptor VEGF-R2 in pediatrics AML may be different from that in adult AML.     

CD7阳性的急性髓系白血病临床及细胞遗传学特征

 目的 研究CD7在急性髓系白血病（AML）患者中的表达情况,分析CD7阳性AML患者临床特点与细胞遗传学特征。方法 对130例AML患者进行研究,用流式细胞仪检测免疫表型,比较CD7阳性AML和CD7阴性AML患者的性别、年龄、外周血白细胞计数、骨髓原始细胞计数等。同时检测CD7阳性患者的染色体核型。结果 AML患者的CD7阳性率为10 %,CD7阳性AML外周血白细胞计数、骨髓原始细胞计数、染色体异常率均高于CD7阴性者。完全缓解率低,生存期短。CD7阳性AML染色体异常率为71.4 %,预后差核型多见。结论 CD7抗原可作为疾病预后差、复发、恶化的指标,CD7阳性的AML患者预后不良。     

Acute myeloid leukemia (AML)-derived mesenchymal stem cells induce chemoresistance and epithelial–mesenchymal transition-like program in AML through IL-6/JAK2/STAT3 signaling

Acute myeloid leukemia (AML) has a high rate of treatment failure due to increased prevalence of therapy resistance. Mesenchymal stem cells (MSCs) in the leukemia microenvironment contribute to chemoresistance in AML, but the specific mechanism remains unclear. The critical role of the epithelial–mesenchymal transition (EMT)-like profile in AML chemoresistance has been gradually recognized. However, there is no research to suggest that the AML-derived bone marrow mesenchymal stem cells (AML-MSCs) induce the EMT program in AML thus far. We isolated AML-MSCs and cocultured them with AML cells. We found that AML-MSCs induced a significant mesenchymal-like morphology in drug-resistant AML cells, but it was scarce in parental AML cells. The AML-MSCs promoted growth of AML cells in the presence or absence of chemotherapeutics in vitro and in vivo. Acute myeloid leukemia MSCs also induced EMT marker expression in AML cells, especially in chemoresistant AML cells. Mechanistically, AML-MSCs secreted abundant interleukin-6 (IL-6) and upregulated IL-6 expression in AML cells. Acute myeloid leukemia cells upregulated IL-6 expression in AML-MSCs in turn. Meanwhile, AML-MSCs activated the JAK2/STAT3 pathway in AML cells. Two JAK/STAT pathway inhibitors counteracted the AML-MSCs induced morphology change and EMT marker expression in AML cells. In conclusion, AML-MSCs not only promote the emergence of chemoresistance but also enhance it once AML acquires chemoresistance. AML-MSCs induce EMT-like features in AML cells; this phenotypic change could be related to chemoresistance progression. AML-MSCs induce the EMT-like program in AML cells through IL-6/JAK2/STAT3 signaling, which provides a therapeutic target to reverse chemoresistance in AML.     

miR-4792 Inhibits Acute Myeloid Leukemia Cell Proliferation and Invasion and Promotes Cell Apoptosis by Targeting Kindlin-3

It has been reported that kindlin-3 expression is closely associated with progression of many cancers and microRNA (miRNA) processing. However, the effects and precise mechanisms of kindlin-3 in acute myeloid leukemia (AML) have not been well clarified. Our study aimed to explore the interaction between kindlin-3 and miR-4792 in AML. In our study, we found that the expression of kindlin-3 was dramatically increased in AML samples and cell lines, and the miR-4792 level was significantly downregulated. Interestingly, the low miR-4792 level was closely associated with upregulated kindlin-3 expression in AML samples. Moreover, introduction of miR-4792 dramatically suppressed proliferation and invasion and induced apoptosis of AML cells. We demonstrated that miR-4792 could directly target kindlin-3 by using both bioinformatics analysis and luciferase reporter assay. In addition, kindlin-3 silencing had similar effects with miR-4792 overexpression on AML cells. Overexpression of kindlin-3 in AML cells partially reversed the inhibitory effects of miR-4792 mimic. miR-4792 inhibited cell proliferation and invasion and induced apoptosis of AML cells by directly downregulating kindlin-3 expression, and miR-4792 targeting kindlin-3 was responsible for the regulation of the proliferation, invasion, and apoptosis of AML cells.     

Haematopoietic cytokines in the biology and treatment of acute myeloid leukaemia

In acute myeloid leukaemia (AML), age has a definite effect on the biology of the disease and also determines the outcome of chemotherapy. AML cells constitutively express mRNA and produce several haematopoietic cytokines. The haematopoietic cytokines: SCF, IL-3, GM-CSF and G-CSF induce leukaemic colonies or activate DNA synthesis in about 80% of AML cases. Both M-CSF and thrombopoietin stimulated AML cell proliferation is seen in vitro in about 50% of cases. Both IL-6 and IL-11 showed little proliferative activity on primary AML cells. The combinations of these cytokines were synergistic in stimulating the proliferation of AML cells. On the other hand, the inhibitory haematopoietic cytokines: TNF-alpha, TGF-beta, IFN-gamma and IL-4 have shown multiple effects on AML blast cell proliferation. In several in vitro systems, haematopoietic cytokines have failed to induce maturation of AML blasts. Only in AML with t(8;21), G-CSF has induced granulocytic maturation of AML blasts in vitro. AML cells with chromosomal abnormalities involving the 21q22 region differentiate in vitro into eosinophils in the presence of IL-5. IL-6 and IFN-alpha have induced megakaryocytic differentiation of blast cells from acute megakaryoblastic leukemia (M7) patients. The haematopoietic cytokines: SCF, IL-3 and GMCSF have protected in vitro AML cells from chemotherapy-induced apoptosis. Many clinical studies have been recently reported evaluating the effect of the haematopoietic cytokines: GM-CSF, G-CSF, IL-3 and PIXY321 as adjuncts to the chemotherapy of AML patients. Most studies have shown these haematopoietic cytokines to be well-tolerated and effective in augmenting neutrophil recovery in elderly AML patients when given after chemotherapy. On the other hand, considerable number of studies using these cytokines before and during chemotherapy to recruit AML cells into cell cycle and thus make them more susceptible to chemotherapy have reaveled no benefit. Several clinical trials have shown promising results after the use of IL-2 either as remission induction therapy in refractory and/or relapsed AML patients or as post-remission consolidative immunotherapy. Haematopoietic cytokines administered after chemotherapy can shorten the duration of neutropenia and hospitalisation without a significant effect on treatment outcome. On the other hand, their use before and during chemotherapy has yielded no benefit, and instead have led to delay of platelet recovery and worse survival rate in some elderly AML patients.     

急性髓系白血病初诊患者组织蛋白酶B、L及血管内皮生长因子mRNA表达及意义

目的：探讨组织蛋白酶B、L（CTSB、CTSL）及血管内皮生长因子（VEGF）在初诊的急性髓系白血病（acute myeloid leukemia,AML）患者中mRNA的表达及其相关性。方法：采用实时荧光定量RT-PCR的方法检测CTSB、CTSL及VEGF mRNA的相对表达水平,分析三者在AML初诊患者中及良性血液病患者中的表达变化及相关性。结果：AML骨髓单个核细胞（bone marrow mononuclear cell,BMMNC）中CTSB、CTSL mRNA的表达水平均明显高于良性血液病患者（P〈0.05）。在AML中存在VEGF mRNA的过度表达,其表达水平明显高于良性血液病组（P〈0.05）。在AML中,CTSB、CTSL与VEGF三者间的mRNA的表达相互间存在显著正相关性。在初诊的AML组中CTSB、CTSL及VEGF高表达与AML缓解率及髓外浸润相关。结论：在AML患者中存在CTSB、CTSL及VEGF的过度表达,且三者存在着显著的相关性;AML患者CTSB、CTSL及VEGF的联合检测及动态观察可作为AML临床辅助诊断及预后判断的指标之一。