Early gene expression of acute myeloid leukemia in response to chemotherapy

The use of gene expression arrays in the evaluation and classification of tumors is becoming increasingly important in a number of malignancies. This is a powerful technique able to disclose interpatient variance in gene expression. Such variation in gene expression may be the cause of different disease outcome and may reflect disease phenotypes or chemoresistance. Acute myeloid leukemia is a malignant disease of the bone marrow where overall long-term disease-free survival is less than 50%. The need for better disease classification and evaluation is consequently evident. Gene expression profiling in acute myeloid leukemia has, in recent years, proven able to distinguish acute myeloid leukemia subclasses and predict clinical outcome and is, as such, a promising technique for improved disease evaluation. The early detection of gene expression in response to chemotherapy may be a novel way of monitoring disease management. The immediate gene response may be an indication of whether the drug of choice is efficient in leukemic cell eradication and may early indicate the need for other therapeutic measures. Furthermore, these early alterations in gene expression could facilitate identification of new treatment targets, thereby enabling better patient care and follow-up in the future.     

SAMHD1基因在初诊急性髓细胞白血病患者中的表达及其临床意义

目的:探讨SAMHD1基因在初诊急性髓细胞白血病（AML)患者中的表达及其临床意义。方法:实时定量PCR方法检测13例成人初诊AML患者与7例非恶性血液病患者SAMHD1 mRNA的表达,分析其临床意义。利用SPSS统计学方法分析SAMHD1基因表达高低与初诊白血病患者临床和实验室特征之间的相关性,采用Kaplan-Meier法以及COX回归模型进行多因素生存分析。结果:SAMHD1基因在AML患者中的表达低于非恶性血液病患者（P＜0.05）,且SAMHD1基因表达高低与患者性别、年龄、初诊时WBC、HGB、PLT、骨髓原始细胞百分比分布差异均无统计学意义;SAMHD1表达高低在预后良好与预后不良组间差异比较有统计学意义（P＜0.05),其中低表达组的OS低于高表达组。结论:SAMHD1基因在AML与非恶性血液病患者中表达差异具有统计学意义,且其可作为影响初诊AML患者OS的独立预后因素。     

Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia

Gemtuzumab ozogamicin (GO) is a chemotherapeutic agent that consists of a humanized anti-CD33 antibody (hP67.6) linked to N-acetyl-calicheamicin 1,2-dimethyl hydrazine dichloride, a potent enediyne antitumor antibiotic. GO was approved conditionally by the Federal Drug Administration in May 2000 as single-agent therapy for first recurrence of acute myeloid leukemia (AML) in patients over the age of 60 years who are unfit for conventional cytotoxic therapy. In this setting, it produces a complete response (CR) rate of 13%, with another 13% achieving CR with inadequate platelet recovery (CRp). The most common adverse effects associated with GO are infusion-related reactions and myelosuppression. GO monotherapy at the dose of 9 mg/m(2) is complicated with hepatic veno-occlusive disease in approximately 5% of cases, particularly prior to or following stem cell transplantation. Attenuated doses of GO or fractionated doses appear to be equally effective and better tolerated. GO has shown remarkable activity in acute promyelocytic leukemia, particularly for the elimination of minimal residual disease. Combinations of GO with chemotherapy as induction or post-remission therapy are promising, and phase III trials are ongoing.     

MH1和PTEN基因在急性髓系白血病中的表达及临床意义

Objective  

The aim of our study was to explore the correlations between both the genes, evolution and prognosis of the disease by detecting the expression of MN1 (meningioma 1) gene and PTEN (phosphatase and tensin homolog) gene in patients with acute myeloid leukemia (AML).     

吉妥珠单抗在CD33阳性急性髓系白血病中的研究进展

急性髓系白血病（acute myeloid leukemia,AML）是一种异质性髓系恶性肿瘤,目前化疗联合造血干细胞移植是主要治疗方法,但是总体预后较差。吉妥珠单抗（gemtuzumab ozogamicin,GO）是一种人源化抗CD33单抗与卡奇霉素结合的抗体偶联药物,主要用于治疗CD33阳性AML。虽然研究发现GO可以改善CD33阳性AML患者的预后,但是仍有部分AML患者并未获益。GO治疗AML的疗效主要与CD33表达及单核苷酸多态性（single nucleotide polymorphism,SNP）、ATP 结合盒亚家族B成员1（ATP-binding cassette subfamily B member 1,ABCB1）基因及SNP、特异的分子生物学和细胞遗传学等因素有关。本文就GO对AML疗效影响因素的研究进展进行综述。     

Over expression of brain and acute leukemia,cytoplasmic and ETS-related gene is associated with poor outcome in acute myeloid leukemia

The high expression of brain and acute leukemia, cytoplasmic (BAALC) and ETS-related gene (ERG) has been reported to influence the outcome in acute myeloid leukemia (AML), but due to limited prospective studies, their role as prognostic factors is unclear. At diagnosis, the prognostic value of BAALC and ERG expression with respect to other cytogenetic and molecular markers was analyzed in 149 AML patients. Patients were divided into quartiles which resulted in the formation of four groups (G1–G4) based on expression values of BAALC and ERG and clinical response defined across groups. Groups with similar survival probabilities were merged together and categorized subsequently as high versus low expressers. Patients with high BAALC and ERG expression had significantly lower overall survival (OS; BAALC: p = 0.001 at 5 years 29.4% vs. 69.8%; ERG: p < 0.0001 at 5 years 4% vs. 50.4%) and disease-free survival (BAALC: p = 0.001 at 5 years 19.5% vs. 69.8%; ERG: p < 0.0001 at 5 years 4.2% vs. 47%). Patients were further stratified combining BAALC and ERG expression in an integrative prognostic risk score (IPRS). After a median follow-up of 54 months (95% CI 45–63 months) among survivors, IPRS for high versus low expressers was a significant predictor for OS (BAALC + ERG: 4% vs. 71.6%, p < 0.0001) and DFS (BAALC + ERG: 4.5% vs. 74.1%, p < 0.0001). In a multivariate model, IPRS of BAALC + ERG expression retained prognostic significance for OS (hazard ratio [HR] 2.96, 95%CI 1.91–4.59, p < 0.001) and DFS (HR 3.61, 95%CI 2.26–5.76, p < 0.001).     

组蛋白去甲基化酶KDM3B在急性髓系白血病中的靶基因鉴定

目的:组蛋白H3赖氨酸9位（H3K9）的甲基化是造血和白血病发生中关键的表观遗传学修饰,由组蛋白甲基化酶和去甲基化酶精确调控。组蛋白H3K9去甲基化酶KDM3B则是一个潜在的白血病发生抑制基因。我们旨在探讨白血病中KDM3B的潜在靶基因。方法:干涉多个急性髓系白血病细胞株中的KDM3B基因后进行微阵列芯片实验,采用基因集富集分析（GSEA）及Venn分析数据,筛选出若干KDM3B潜在的靶基因,并用实时定量PCR对CDKN1A基因的结果进行验证。结果:对比GSEA 的分子标签数据库中标志基因集（H）和已建立的基因集(C2),在NB-4和PLB-985细胞中（分别影响）,与KDM3B正相关的基因分别有2 375和2 007个,其中P＜0.05的基因分别有89和67个;与KDM3B负相关的基因分别有1 882和2 250个,其中P＜0.05的基因分别有62和67个,包括FLT3、NRAS、EVI1和IL4等基因。对比GSEA 的分子标签数据库中染色体位置（C1）、已建立的基因集（C2）、模序（C3）、肿瘤相关基因集（C4）、GO 基因集（C5）、致瘤基因集（C6）、免疫学基因集（C7）和标志基因集（H）,在NB-4和PLB-985细胞中（共同影响）,与KDM3B正相关的基因有4 815个,其中P＜0.05的基因有130个;与KDM3B负相关的基因有4 400个,其中P＜0.05的基因有97个,包括POU5F1和CDKN1A等基因。干扰NB-4和PLB-985细胞中KDM3B基因的表达,我们选取影响最强的600个探针用Venn分析,在两种细胞系中表达均下降的基因有16个,包括血液病相关基因CCDN3、TRIM24、MAPKI3、SOX6等;在NB-4细胞中表达降低但在PLB-985细胞中表达升高的基因有17个,包括RARRES3和CD58等基因。实时定量PCR结果显示干扰PLB-985细胞中KDM3B后CDKN1A的表达是对照组的1.18倍。结论:KDM3B调控急性髓系白血病相关基因,CDKN1A是一个潜在的KDM3B靶基因。     

Cell cycle control in acute myeloid leukemia

Acute myeloid leukemia (AML) is the result of a multistep transforming process of hematopoietic precursor cells (HPCs) which enables them to proceed through limitless numbers of cell cycles and to become resistant to cell death. Increased proliferation renders these cells vulnerable to acquiring mutations and may favor leukemic transformation. Here, we review how deregulated cell cycle control contributes to increased proliferation in AML and favors genomic instability, a prerequisite to confer selective advantages to particular clones in order to adapt and independently proliferate in the presence of a changing microenvironment. We discuss the connection between differentiation and proliferation with regard to leukemogenesis and outline the impact of specific alterations on response to therapy. Finally, we present examples, how a better understanding of cell cycle regulation and deregulation has already led to new promising therapeutic strategies.     

免疫疗法治疗急性髓系白血病的新进展

急性髓系白血病（acute myeloid leukemia,AML）是最常见的白血病,发病率居高不下,尽管随着科技的发展,可以延长其生存期,但对新型治疗方法的需求仍十分紧迫。当前的癌症免疫学和免疫疗法概念具有相关性,因此可以考虑从免疫治疗的角度上治疗AML,但在设计针对这种白血病的合理免疫疗法时,还应考虑AML免疫失调的独特方面。本文主要从改善免疫系统和白血病靶标之间的平衡,直接针对白血病的抗体,T细胞和NK细胞进行干预,使用呈递白血病抗原的增强抗原呈递细胞重新设计并重新激活患者T细胞的疫苗三方面进行综述。     

AML1-ETO融合基因转阴对急性髓细胞白血病预后的影响

目的:探讨AML1-ETO融合基因阳性表达的急性髓细胞白血病（acute myelocytic leukemia,AML）患者治疗后融合基因转阴及转阴时间长短对AML患者预后的影响。方法:对2012年1月1日至2016年12月31日在中国医科大学附属盛京医院住院治疗的35例初诊AML1-ETO融合基因阳性AML患者的临床资料进行回顾性分析,总结其形态学、免疫学和分子生物学特征,用 Kaplan-Meier 曲线评估患者生存情况。结果:35例患者男女比例 1.33∶1,中位年龄为34岁(15~71岁)。中位随访时间为16(4~61)个月,诱导缓解率为82.9%,3个疗程或以上缓解占14.3%(n=5),始终未缓解占2.9%(n=1),复发率35.3％(n=12),复发中位时间 12（6~20）个月。其中11例治疗后融合基因转阴,包括3个月内转阴占63.6%（n=7）,大于3个月转阴占36.4%（n=4）。单因素分析表明AML1-ETO融合基因转阴患者OS和PFS高,预后较好,AML1-ETO融合基因转阴时间长短对患者长期生存的影响无统计学意义（P=0.707）。结论:AML1-ETO融合基因转阴的AML患者预后较好,AML1-ETO融合基因转阴时间长短对患者的长期生存无明显影响。     

EZH2 在急性髓系白血病病程中的表达和对预后判断的意义研究

目的：探讨DNA 甲基转移酶（DNAmethyltransferase,DNMT 1）与EZH 2 在急性髓系白血病（acutemyeloidleukemia,AML ）中的表达及其相关性。方法：采用荧光定量PCR（fluorescencequantitativePCR ,FQ-PCR）检测大连医科大学附属第二医院2014年1月至2015年1 月50例初治AML 患者骨髓细胞中DNMT 1 与EZH 2 mRNA 的表达水平,分析DNMT 1 表达水平与临床特征和预后的关系以及与EZH 2 的相关性。结果：50例AML 患者骨髓细胞中DNMT 1 mRNA 的表达显著高于30例正常供者（2.72± 0.73vs . 0.89±0.27,P < 0.01）;EZH 2 的表达水平也显著高于正常供者（4.39± 1.06vs . 1.87± 0.33,P < 0.01）;EZH 2 与DNMT 1 的表达水平呈显著正相关（r = 0.51,P = 0.002）;DNMT 1 表达水平与外周血幼稚细胞比例≥ 60%（P < 0.05）、WBC≥ 50× 10⁹/L （P < 0.05）呈显著相关;DNMT 1 高表达组患者中位生存时间15个月（95%CI 为9～19个月）,显著低于DNMT 1 低表达组患者的32个月（95%CI 为27～40个月,P =0.006）。结论：DNMT 1 和EZH 2 在AML 患者中均高表达,两者表达水平呈正相关,DNMT 1 与AML 患者预后不良相关。     

Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia

Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.     

伴有t(8;21)的急性髓系白血病研究进展

伴有染色体t(8;21)(q22;q22)易位及AML1-ETO融合基因是急性髓系白血病(AML)的独立亚型,预后较好.虽然以大剂量阿糖胞苷(HD Ara-C)为主的联合化疗在t(8;21)-AML取得了较高的缓解率,但是特异性靶向AML1-ETO的治疗方案可能是治愈该类AML的有效策略.现就AML1-ETO融合基因相关研究及其靶向治疗的研究进展进行综述.     

Role of blast cell immunophenotyping for the diagnosis and prognosis of acute myeloid leukemia.

Bone marrow blast cell antigen expression from 86 patients with de novo acute myeloid leukemias (AML) was studied and correlated with FAB classification and clinical outcome. Among a panel of 14 monoclonal antibodies routinely used for the diagnosis of acute leukemias we studied the expression of six antibodies (CD13, CD15, VIM2, CD33, CD14, CD34) of the granulomonocytic lineage and found that some of them were useful for diagnosis and/or prognosis. For FAB subclassification of AML, the CD13 or VIM2 antigen expression was of no benefit. Monocytic leukemias (M4 + M5PD + M5WD) more frequently expressed CD34 antigen (28/31) than granulocytic (M1 + M2 + M3) subtypes (33/53) (P < 0.01). Finally, the most striking differences were found with CD14 antigen expression: CD14 antigen was more frequently expressed in M4 + M5 leukemias (21/31) than in M1 + M2 + M3 subtypes (12/33) (P < 0.01). The mean percentage of CD14 positive blast cells was accordingly higher in monocytic leukemias than in granulocytic leukemias and the difference was highly significant (P < 0.0001). The CD15 antigen was more frequently expressed in differentiated leukemias (M2 + M3 + M4 + M5WD) (35/44) than in poorly differentiated forms (M1 + M5PD) (17/37) (P < 0.001). The statistical difference was higher when the mean percentage of CD15 positive blast cells were compared (P < 0.0003). Moreover these latter percentages were different in M1 and M2 subtypes (P < 0.003). The blast cell expression of CD13, CD14, CD15 or CD33 was not predictive of the length of CR or survival. Moreover, our results support previously published findings suggesting a longer overall survival duration for patients whose leukemic cells do not express the CD34 antigen (P < 0.01). We also confirm that patients with the more differentiated subtypes of AML (CD13-, CD34+) tend to survive longer than patients with the less differentiated subtypes of AML (CD13-, CD34+) (P < 0.001).     

FLAG方案与CAG方案治疗复发、难治性急性髓系白血病的疗效比较

目的：评价并比较FLAG方案与CAG方案治疗复发、难治性急性髓系白血病（acute myeloid leukemi-a,AML）的疗效及安全性。方法：将2004年1月至2011年3月于我院接受化疗的复发、难治性AML患者74例,按治疗方案分成FLAG组和CAG组,对2组的疗效及不良反应进行分析比较。结果：FLAG组完全缓解率（CR）为61.5%,总有效率为76.9%;CAG组CR为35.4%,总有效率为50%,组间比较差异有显著性意义（P〈0.05）。原发难治AML、复发性AML、M1型、M2型、M5型及由骨髓增生异常综合征（myelody splastic syn-drome,MDS）转化而来的复发、难治性AML的CR率和总有效率,FLAG组均高于CAG组,组间比较差异有显著性意义（P均〈0.05）。2组的血液学不良反应主要是骨髓抑制,非血液学不良反应较少。结论：CAG方案和FLAG方案均为复发、难治性AML的有效治疗方案,但FLAG方案CR率和总有效率高,不良反应可耐受,可进一步扩大临床应用。