HTLV-1病毒蛋白Tax和HBZ协同促进成人T细胞白血病发生的机制

人类T细胞白血病1型病毒(Human T-cell leukemia virus type 1,HTLV-1)是与人类疾病发生密切相关的逆转录病毒。该病毒的感染可引起成人T细胞白血病(Adult T-cell leukemia,ATL)等多种疾病的发生。Tax和HBZ(HTLV-1 basic zipper protein)是由HTLV-1前病毒编码的两个关键病毒蛋白,它们被认为在HTLV-1病毒的复制、生存和致癌过程中发挥了至关重要的作用。本文就Tax和HBZ的蛋白结构以及它们在调控病毒转录、细胞生长和凋亡、病毒潜伏期,最终协同促进成人T细胞白血病发生过程中发挥的作用作一综述。     

Leukemia stem cells: the root of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a chromosome translocation that generates the Bcr-Abl oncogene encoding a constitutive kinase activity. Despite remarkable success in controlling CML at chronic phase by Bcr-Abl tyrosine kinase inhibitors (TKIs), a significant proportion of CML patients treated with TKIs develop drug resistance due to the inability of TKIs to kill leukemia stem cells (LSCs) that are responsible for initiation, drug resistance, and relapse of CML. Therefore, there is an urgent need for more potent and safer therapies against leukemia stem cells for curing CML. A number of LSCassociated targets and corresponding signaling pathways, including CaMKII-γ, a critical molecular switch for co-activating multiple LSC-associated signaling pathways, have been identified over the past decades and various small inhibitors targeting LSC are also under development. Increasing evidence shows that leukemia stem cells are the root of CML and targeting LSC may offer a curable treatment option for CML patients. This review summarizes the molecular biology of LSC and itsassociated targets, and the potential clinical application in chronic myeloid leukemia.     

MicroRNAs and response to therapy in leukemia

A variety of epigenetic factors involved in leukemia pathogenesis. Among various epigenetic factors, microRNAs (miRNAs) have emerged as important players, which affect a sequence of cellular and molecular signaling pathways. Leukemia is known as progressive cancer, which is related to many health problems in the world. It has been shown that the destruction of the blood-forming organs could lead to abnormal effects on the proliferation and development of leukocytes and their precursors. Despite many attempts for approved effective and powerful therapies for patients with leukemia, finding and developing new therapeutic approaches are required. One of the important aspects of leukemia therapy, identification of underlying cellular and molecular mechanisms involved in the pathogenesis of leukemia. Several miRNAs (ie, miR-103, miR-101, mit-7, let-7i, miR-424, miR-27a, and miR-29c) and play major roles in response to therapy in patients with leukemia. miRNAs exert their effects by targeting a variety of targets, which are associated with response to therapy in patients with leukemia. It seems that more understanding about the roles of miRNAs in response to therapy in patients with leukemia could contribute to better treatment of patients with leukemia. Here, for the first time, we summarized various miRNAs, which are involved in response to therapy in the treatment patients with leukemia.     

急性早幼粒细胞白血病（APL）中t（15;17）染色体易位的分子机制研究

对急性早幼粒细胞白血病中ｔ（１５;１７）染色体易位的分子生物学研究显示,１７号染色体上的维甲酸受体α（ＲＡＲＡ）基因与１５号染色体上的ＰＭＬ基因并置,并产生ＰＭＬ－ＲＡＲＡ融合基因。我们以前的工作证明ＡＰＬ患者中ＰＭＬ基因断裂点集中于２个限区域,即ＰＭＬ－ｂｃｒ１和ＰＭＬ－ｂｃｒ ２,二者相距约１０ｋｂ。本文确定了ＰＭＬ－ｂｃｒ １的ＤＮＡ顺序,并确定了一例ＡＰＬ患者染色体相互易位接合部的基本结构     

microRNA在急性淋巴细胞白血病中的作用

MicroRNAs(miRNAs)是一类非编码小RNA分子,其通过降解mRNAs或抑制mRNAs翻译来负调控基因表达并可能调控着几乎每一个细胞生理进程.急性淋巴细胞白血病(ALL)是儿童时期最常见的血液肿瘤,miRNA的异常表达谱对于ALL的发病机制与临床应用有至关重要的作用,因此miRNAs已迅速成为ALL潜在的治疗靶点.     

Identification of complement C3f‐desArg and its derivative for acute leukemia diagnosis and minimal residual disease assessment

Therapeutic conditions for acute leukemia (AL) mainly rely on diagnosis and detection of minimal residual disease (MRD). However, no serum biomarker has been available for clinicians to make diagnosis of AL and assessment of MRD. In this study, we performed bead fractionation/MALDI‐TOF‐MS analysis on sera from patients with AL. Support vector machine algorithm was used to obtain diagnostic model that discriminated proteomic spectra of patients with AL from that of controls. Twenty‐six features with p<0.00001 had optimal discriminatory performance, with 97% sensitivity and 100% specificity. Statistical analysis revealed that two peptides with m/z 1778 and 1865 were gradually decreased in their relative intensities with increase of remission degree. Moreover, the peptide with m/z 1865 was also found to be correlated with AL types. With FT‐ICR‐MS detection, both the peptides were identified as fragments of complement C3f. Linear regression analysis showed that the combined use of them could discriminate PML/RARα positive M3 from molecular remission M3. Two fragments of complement C3f were significantly correlated with MRD levels and could be used for clinical practice in MRD assessment.     

PML Suppresses Influenza Virus Replication by Promoting FBXW7 Expression

Virologica Sinica - Influenza A viruses (IAV) are responsible for seasonal flu epidemics, which can lead to high morbidity and mortality each year. Like other viruses, influenza virus can hijack...     

Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C2 and C6 positions

Acute myeloid leukemia (AML) is a clonal disorder of hematopoietic progenitor cell. In AML, a mutation in FLT3 is commonly occurs and is associated with poor prognosis. We have previously reported that thieno[2,3-d]pyrimidine derivative compound 1 exhibited better antiproliferative activity against MV4-11 cells which harbor mutant FLT3 than AC220, which is a well-known FLT3 inhibitor, and has good microsomal stability. However, compound 1 had poor solubility. We then carried out further structural modification at the C₂ and the C₆ positions of thieno[2,3-d]pyrimidine scaffold. Compound 13b, which possesses a thiazole moiety at the C₂ position, exhibited better antiproliferative activity than compound 1 and showed increased solubility and moderate microsomal stability. These results indicate that compound 13b could be a promising potential FLT inhibitor for AML chemotherapy.     

JDV与三种牛反转录病毒相互关系的初步研究

为研究JDV与其它三种牛反转录病毒BIV、BLV、BFV的相互作用关系,将以JDV、BIV、BLV、BFV的LTR为启动子,以Luc为报告基因的质粒和以上病毒反式激活因子的表达质粒共转染BL12细胞系,通过瞬时表达分析试验证明了JDV和BIV的LTR和Tat之间亲缘关系很近,能够相互激活;JDV Tat可以反式激活BLVLTR,BLV Tax不能激活JDV LTR;JDV LTR上存在BFV Tas的应答元件;BLV、BFV和BIV的LTR和反式激活因子间不存在相互激活.     

JDV与三种牛反转录病毒相互关系的初步研究

为研究JDV与其它三种牛反转录病毒BIV、BLV、BFV的相互作用关系,将以JDV、BIV、BLV、BFV的LTR为启动子,以Luc为报告基因的质粒和以上病毒反式激活因子的表达质粒共转染BLl2细胞系,通过瞬时表达分析试验证明了JDV和BIV的LTR和Tat之间亲缘关系很近,能够相互激活;JDV Tat可以反式激活BLVLTR,BLVTax不能激活JDVLTR;JDVLTR上存在BFVTas的应答元件;BLV、BFV和BIV的LTR和反式激活因子问不存在相互激活。     

成人急性髓性白血病SOCS-1 基因及其甲基化的研究

目的:通过检测成人急性髓性白血病中SOCS-1基因表达水平及其甲基化水平,研究其在白血病发病中的作用。方法:运用甲基化特异性PCR(Methylation specific PCR,MSP)方法,对24例急性髓性白血病患者和4株白血病细胞株(Jurkat、Raji、U 937、NALM 17),进行SOCS-1基因甲基化水平的研究;同时运用Real-time PCR法定量分析SOCS-1基因表达水平。以10例健康人为正常对照组。结果:24例成人急性髓性白血病患者中,15例有SOCS-1基因甲基化(62.5%),而正常对照组无SOCS-1基因甲基化(0%),二者有显著差异(P<0.05);SOCS-1基因甲基化组与无SOCS-1基因甲基化组相比较,其SOCS-1基因相对表达量明显减少(P﹤0.05);与患者临床病理特征相结合比较,发现SOCS-1基因的甲基化与患者年龄、性别和病程阶段无相关。4株白血病细胞株中,Jurkat和U 937表现有SOCS-1甲基化(50%),Raji和NALM 17无SOCS-1甲基化,前者SOCS-1基因表达量较后者也明显降低(P<0.05)。结论:SOCS-1基因在成人急性髓性白血病中甲基化水平明显增高,且SOCS-1基因甲基化后表达水平受到抑制,提示SOCS-1基因及其甲基化在急性髓性白血病的发生发展中可能具有一定作用。     

L6565小鼠白血病病毒诱发小鼠白血病

为探讨病毒与白血病发生的关系,我们用L6565小鼠白血病病毒（L6565MLV）悬液感染乳鼠,每周观察小鼠的发病情况及病理变化,并用逆转录一聚合酶链反应（RT－PCR）动态检测小鼠体内病毒核酸的分布,结果发现：小鼠感染病毒后3－5周,其脾脏和淋巴结呈早期白血病的病理改变,至第10－12周小鼠发生淋巴细胞白血病,表现出耸毛、活动减少、腹膨胀等症状。病毒核酸于感染后第2周首先在小鼠胸腺、脾脏检测到,随时间延长,病毒核酸广泛分布在外周血、胸腺、脾脏、淋巴结等多种脏器组织中。本实验表明L6565小鼠白血病病毒可诱发小鼠白血病,其机制可能与病毒促使淋巴细胞向白血病细胞转化有关。     

L6565小鼠白血病病毒诱发小鼠白血病

为探讨病毒与白血病发生的关系,我们用L6565小鼠白血病病毒(L6565MLV)悬液感染乳鼠,每周观察小鼠的发病情况及病理变化,并用逆转录一聚合酶链反应(RT-PCR)动态检测小鼠体内病毒核酸的分布.结果发现小鼠感染病毒后3～5周,其脾脏和淋巴结呈早期白血病的病理改变.至第10～12周小鼠发生淋巴细胞白血病,表现出耸毛、活动减少、腹膨胀等症状.病毒核酸于感染后第2周首先在小鼠胸腺、脾脏检测到,随时间延长,病毒核酸广泛分布在外周血、胸腺、脾脏、淋巴结等多种脏器组织中.本实验表明L6565小鼠白血病病毒可诱发小鼠白血病,其机制可能与病毒促使淋巴细胞向白血病细胞转化有关.     

Expression analysis of Foxp3 in T cells from bovine leukemia virus infected cattle

In the present study, we monitored Foxp3⁺ T cells in bovine leukemia virus (BLV)‐infected cattle. By flow cytometric analysis, the proportion of Foxp3⁺CD4⁺ cells from persistent lymphocytotic cattle was significantly increased compared to control and AL cattle. Interestingly, the proportion of Foxp3⁺CD4⁺ cells correlated positively with the increased number of lymphocytes, virus titer and virus load, whereas it inversely correlated with IFN‐γ mRNA expression, suggesting that Foxp3⁺CD4⁺ T cells in cattle have a potentially immunosuppressive function. Further studies are necessary to elucidate the detailed mechanism behind the increased Treg during BLV infection.     

几种药物对HL-60细胞的诱导分化作用及其过程中蛋白激酶C活力分布的变化

本文就HHT、RA、WB_(852)对HL-60细胞的诱导分化作用及此过程中PKC活力在细胞胞浆部分及膜溶脱部分的变化进行研究。结果表明,在适当的用药浓度下,从细胞生长抑制情况、形态学观察及NBT还原能力测定判断,三种药物对HL-60细胞有明显的诱导分化作用。PKC活力分布变化的研究结果表明,用药组细胞胞浆部分酶活力有不同程度的下降,尤在用药早期(约6h以前)下降显著;而膜部分PKC活力则表现上升、或下降,或活力相差不大的结果。暗示在信息传递过程中起核心作用的PKC对不同的胞外刺激可能采取不同的应答方式。PKC的作用可能主要发生在信息传递的早期。     

RNA结合蛋白质HuR通过增加YAP1 mRNA稳定性促进白血病细胞增殖

RNA结合蛋白质人类抗原R(Hu R)与多种实体肿瘤的发生发展密切相关,但其在人急性髓系白血病(acutemyeloidleukemia,AML)中的功能和分子机制仍未阐明。本研究收集了30例临床初诊的AML病人和30例正常对照的外周血,分离单个核细胞,进行RT-qPCR法检测。结果显示,与正常对照相比,HuR在AML病人中呈显著表达上调趋势(3.17±1.12,P<0.05)。在AML细胞系HL-60中的功能检测发现,敲低内源性HuR后,对HL-60细胞培养12 h(0.17±0.07),24 h(0.38±0.05),36 h(0.51±0.03),48 h(0.69±0.05),60 h(0.92±0.08)和72 h(1.04±0.10)的增殖产生抑制作用(P<0.05)。同时,阻滞在G1期(47.3%±5.4)的HL-60细胞比例显著升高(P<0.05),而S期(37.5%±6.9)细胞比例显著降低(P<0.05)。相反,HuR的表达抑制对HL-60细胞向单核系分化产生促进作用。RNA免疫共沉淀法检测发现,HuR可与Hippo通路的Yes相关蛋白1关键效应基因(YAP1)的mRNA结合。后续的RNA稳定性检测发现,HuR的结合可以增强YAP1 mRNA的稳定性,进而促进YAP1的表达,并进一步影响YAP1下游基因的转录。综上所述,RNA结合蛋白质HuR可通过促进Hippo通路YAP1的表达参与AML发生发展的调节。     

LncRNA882 regulates leukemia inhibitory factor (LIF) by sponging miR-15b in the endometrial epithelium cells of dairy goat

Despite the fact that long noncoding RNAs (lncRNAs) play roles in almost all biological processes, little is known about their biological function in the endometrium during the formation of endometrial receptivity. In this study, a comprehensive analysis of lncRNAs in goat endometrial tissues on Day 5 (prereceptive endometrium, PE) and Day 15 (receptive endometrium, RE) of pregnancy was performed by using RNA-Seq. As a result, 668 differentially expressed lncRNAs (DELs) were found between the PE and RE. Further study showed that lncRNA882, regulated by estrogen (E2) and progestin (P4), could act as competing endogenous RNAs (ceRNAs) for miR-15b, which inhibited the expression of transforming growth factor-b-activated kinase 1 binding protein 3 (TAB3) and then indirectly regulated the level of leukemia inhibitory factor (LIF). This was helpful for the formation of endometrial receptivity in dairy goats. In conclusion, we elucidated the endometrium lncRNA profiles of PE and RE in dairy goats; lncRNA882 acted as a ceRNA for miR-15b and then indirectly regulated the level of LIF in goat endometrial epithelium cells. Thus, this study helped us to better understand the molecular regulation of endometrial receptivity in dairy goats.     

次黄嘌呤鸟嘌呤磷酸核糖转移酶研究进展

次黄嘌呤鸟嘌呤磷酸核糖转移酶(Hypoxanthine-guanine phosphoribosyltransferase, HPRT)是一种细胞质酶, 在体内广泛存在, 它不仅参与嘌呤碱基的补救合成途径, 而且关系到嘌呤类药物的代谢, 是调控该类药物药理效应和毒性反应的关键酶。其基因突变可影响酶的活性, 不仅可能导致不同临床表现的代谢疾病的发生, 而且影响体内嘌呤类药物的代谢。同时, HPRT作为管家基因, 是诊断许多疾病的靶点基因。文章概括了HPRT研究的新进展, 通过总结国内外研究现状, 发现HPRT的研究既推动了嘌呤类药物个体化用药的发展及新药物的研发, 又促进了HPRT突变相关遗传代谢疾病的诊断和治疗。     

Thyrotropin releasing hormone receptors in regulation of prolactin gene expression in GH cells

Calf thymus DNA polymerase β and mammalian type C retroviral DNA polymerases are strongly inhibited by low concentrations (1–2mM) of inorganic phosphate (Pi). A detailed analysis of this phenomenon revealed that Pi-mediated inhibition: a) requires the presence of Mn²⁺ (Mg²⁺ neither supports nor relieves this inhibition; b) is strongly affected by the stoichiometric relationship between Mn²⁺ and Pi concentrations; c) is competitive with respect to deoxynucleoside triphosphate (dNTP) concentration, and d) increasing the concentration of substrate or non-substrate dNTPs in reaction mixtures raised the concentration of Mn²⁺ at which significant inhibition by a fixed concentration of Pi was first seen. These findings suggested that Mn²⁺, dNTPs, and Pi may interact in Pi-mediated inhibition. Thin-layer chromatographic analysis revealed the formation of an Mn-dNTP-Pi complex, while Mg²⁺ did not participate in such complex formation. We propose that it is this tripartite complex which is responsible for the Pi-mediated inhibition of sensitive DNA polymerases.