MSI2-NOTCH1通路在成人急性淋巴细胞白血病中表达及丙戊酸钠对其作用研究
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摘要
背景：
成人急性淋巴细胞白血病(acute lymphoblastic leukemia, ALL)是一组在临床和生物学上存在很大异质性的恶性肿瘤,其发病机制尚不清楚。尽管随着科学技术不断提高,成人ALL诱导缓解率已经有了很大提高,但其长期生存仍不尽人意。因而,进一步阐明成人ALL发病机制、寻找有效分子靶点以及完善其临床预后评价体系是当前提高治愈率的首要任务。MSI2-NOTCH1通路基因包括MSI2(Musashi-2)、NUMB、NOTCH1、c-MYC和HES1等基因,参与胚胎发育、干细胞自我更新、组织细胞分化等多种生理功能。一些研究显示,这些基因突变或异常表达与多种血液肿瘤发生或进展有密切的关系,但系统地分析这些基因表达水平与成人ALL患者预后关系的研究尚未见报道。组蛋白乙酰化酶和去乙酰化酶的动态平衡直接影响染色质的结构,调节很多基因的转录。组蛋白去乙酰化酶异常参与包括白血病在内多种肿瘤的发病机制,丙戊酸钠(valproic acid, VPA)等组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACIs)已成为肿瘤治疗一个热点。在一些肿瘤中,VPA能激活NOTCH1通路而抑制细胞生长；而另一些肿瘤中,VPA却下调NOTCH1表达水平。然而,MSI2-NOTCH1通路在VPA抑制ALL细胞生长分子机制中的作用仍不明了。为此,本研究分成两个部分分别阐述MSI2-NOTCH1通路基因在成人ALL中表达的临床意义和该通路基因在VPA抑制ALL细胞生长分子机制中的作用。
第一部分：MSI2-NOTCH1通路基因在成人急性淋巴细胞白血病中表达及其临床意义研究
目的：
探讨MSI2-NOTCH1通路基因表达水平与成人急性淋巴细胞白血病(ALL)患者预后的关系。
方法：
用实时定量PCR方法检测144例初发成人ALL患者骨髓单个核细胞和正常对照中的MSI2、NUMB、NOTCH1、c-MYC和HES1基因表达水平,比较这些基因在ALL和正常对照之间以及不同ALL亚型之间表达差别；筛选出与ALL患者的总生存(overall survival, OS),无事件生存(event free survival, EFS)或无复发生存(relapse free survival, RFS)密切相关的基因,并分析该基因表达水平与其他临床和实验室指标之间的关系；动态分析该基因表达水平在初发时和完全缓解时变化；比较该基因表达与其他MSI2-NOTCH1通路基因之间的关系；用siRNA (small interfering RNA)干扰方法下调该基因,用MTT法、集落培养、Annexin V/PI双染色法观察对THP-1细胞生长和凋亡影响,用定量PCR和western blot检测MSI2、NUMB和NOTCH1表达并分析它们之间的关系。
结果：
(1)与正常对照相比,ALL患者中的MSI2表达水平明显升高(p<0.001),而NUMB和NOTCH1明显减低(p值均小于0.001),两组的c-MYC和HES1基因表达水平无明显差别(p值分别为0.645和0.108)。(2) B-ALL患者的NOTCH1和HES1表达水平明显低于T-ALL患者(p值分别为0.007和0.002),但两组的MSI2、NUMB和c-MYC表达水平没有明显差别(p值均大于0.05)。(3)用Kaplan-Meier分析筛选后,在MSI2-NOTCH1通路基因中,MSI2表达水平与ALL患者预后密切相关(OS和EFS的p值均为0.002)。(4)在成人B-ALL患者中,MSI2高表达组的中位OS、EFS和RFS分别为7.30月、5.90月和5.50月,明显短于MSI2低表达组(分别为14.37月、9.26月和9.27月,p值分别为0.007、0.002和0.179)；用Backward LR Cox模型纠正白细胞数、t(9;22)/BCR-ABL和IK6等因素后,MSI2高表达组的生存仍明显差于低表达组,两组OS、EFS和RFS的p值分别为0.001、<0.001和0.043。(5)在成人B-ALL患者中,MSI2表达水平与年龄、性别、白细胞计数、t(9;22)/BCR-ABL、MLL重排和IKZF1基因IK6变异体没有明显相关性；但MSI2高表达组中复杂异常、近3倍体和9p-等少见不良核型率(n=5,17.3%)高于MSI2低表达组(n=3,3.4%,p=0.019)；(6)在10例配对标本中,与初发时相比,完全缓解时MSI2表达水平明显减低(p=0.007)。(7)在正常对照中,MSI2与NUMB、NOTCH1、c-MYC和HES1表达水平呈正相关(p值分别为<0.001、<0.001、0.027和0.003)；在B-ALL和T-ALL患者中,MSI2与NUMB、NOTCH1表达水平呈正相关(p值均小于0.05),但与c-MYC和HES1表达水平没有明显相关性(p值均大于0.05)。(8)沉默THP-1细胞MSI2基因24小时后,小干扰组细胞活力为51.39±7.92%,明显低于阴性对照组(100%,p=0.005)；培养9天后,小干扰组细胞集落数为7.50±1.53,明显低于阴性对照组(35.75±7.46,p<0.001)；小干扰组24和48小时凋亡率均明显高于阴性对照组(p值分别为0.008和0.001),并伴随Caspase-3和Parp剪切增加。(9)小干扰THP-1细胞MSI224和48小时,与阴性对照相比,NUMB和NOTCH1mRNA表达没有明显差别(p值均大于0.05)。
结论：
(1)在MSI2-NOTCH1通路基因中,MSI2高表达是成人ALL患者预后不良因素之一,是成人B-ALL患者预后不良独立危险因素之一。(2)下调MSI2表达水平能减低白血病细胞活力、导致细胞凋亡增加。(3)与正常细胞不同,ALL细胞中的MSI2表达水平增高不能激活NOTCH1信号。
第二部分：丙戊酸钠对急性淋巴细胞白血病的MSI2-NOTCH1通路影响研究
目的：
探讨MSI2-NOTCH1通路基因在组蛋白去乙酰化酶抑制剂丙戊酸钠(VPA)抑制急性淋巴细胞白血病(ALL)生长分子机制中的作用。
方法：
用MTT法、流式细胞术检测不同浓度VPA对T-ALL细胞株Jurkat、MOLT4和CEM细胞和B-ALL细胞株NALM6细胞生长、细胞周期和凋亡的影响；0.8、1.6、2.4和3.2mM浓度的VPA作用NALM6、Jurkat、MOLT4和CEM细胞24小时,定量PCR和Western blot检测凋亡相关蛋白、MSI2-NOTCH1通路基因及其下游基因表达变化。用MTT法、流式细胞术和Western blot观察γ-分泌酶抑制剂DAPT联合VPA作用Jurkat和CEM细胞后对其细胞生长、周期、凋亡和凋亡相关蛋白以及NOTCH1通路蛋白影响。NOTCH配体Jagged-1激活NOTCH信号24小时后,MTT法检测其对1.6、2.4、3.2和4.0mM浓度的VPA抑制Jurkat细胞生长的影响；60uM10058-F4联合不同浓度VPA作用Jurkat和CEM细胞后,用MTT法、Annexin V/PI和Western blot观察细胞生长、凋亡及凋亡相关蛋白变化。
结果：
(1)用0.2-12.8mM浓度VPA作用Jurkat、MOLT4、CEM和NALM6细胞,24和48小时4株细胞生长均受到不同程度抑制,其24小时IC50分别为5.37、7.02、4.69和7.56mM;1.6mM VPA作用Jurkat、MOLT4、CEM和NALM6细胞24小时,其G0/G1细胞比例分别为63.27±2.75%、60.94±3.28%、53.50±2.27%和73.95±1.77%,均明显高于对照组(49.56±2.63%、43.33±1.76%、43.46±2.01%和61.39±3.58%)；实验浓度VPA作用Jurkat、MOLT4、CEM和NALM6细胞24小时,其凋亡率呈现浓度依赖性增加,伴随BIM、Caspase-8、Caspase-9、Caspase-3和Parp不同程度激活；(2)实验浓度VPA作用Jurkat、MOLT4、CEM和NALM6细胞24小时,与对照组相比,MSI2变化不明显；NUMB、p27和非磷酸化RB均出现不同程度上调；c-MYC.CDK4.CDK6和磷酸化RB均出现下调；在Jurkat、 MOLT4和CEM细胞中,NOTCH1出现明显下调,但在NALM6细胞中NOTCH1没有变化；ICN1在Jurkat和CEM细胞中明显下调,在MOLT4和NALM6细胞中没有检测到。定量PCR检测NOTCH1和c-MYC mRNA表达水平,其变化与蛋白水平一致。以0.8mM VPA作用Jurkat细胞6h、12h、24h和2d以及用实验浓度SAHA作用Jurkat细胞,均能观察到NOTCH1、ICN1和c-MYC蛋白下调。(3)15μM DAPT联合不同浓度VPA作用Jurkat和CEM细胞24小时,DAPT处理后不同实验浓度VPA组生长抑制率均明显高于DMSO处理的相应VPA组,p值分别为0.004和0.001。但DAPT组不能增加VPA对Jurkat和CEM细胞的G0/G1阻滞、Caspase-3、Parp和LC3的激活。(4)用Jagged-1激活Jurkat细胞NOTCH信号,Jagged-1处理后不同实验浓度VPA组24小时抑制率均明显低于IgG处理的相应VPA组,p=0.019。(5)用c-MYC抑制剂10058-F4处理Jurkat和CEM细胞后,加不同实验浓度VPA作用24小时,MTT法检测显示10058-F4处理后不同实验浓度VPA组的生长抑制率均明显高于相应VPA组,p值分别为0.012和0.007; Annexin V/PI双染法检测显示,用10058-F4处理的不同实验浓度VPA组的细胞凋亡率均明显高于DMSO处理的相应VPA组,p值分别为0.038和0.037；在Jurkat和CEM细胞中,10058-F4能进一步增加0.8和1.6mM VPA对Parp和Caspase-3的剪切。
结论：
(1)VPA能通过诱导细胞凋亡和阻滞细胞周期而抑制ALL细胞生长；
(2)VPA能通过下调c-MYC表达实现对ALL细胞生长抑制。
(3)VPA还能通过下调NOTCH1转录水平,抑制NOTCH1信号实现对Jurkat和CEM细胞生长抑制。
Backgroud:
Adult acute lymphoblastic leukemia (ALL) is a group of malignant tumors with marked clinical and biological heterogeneity and its pathogenesis remains unclear. With science and technology development, the induction remission rate in adult ALL has been greatly improved, but its long survival remains poor. Thus, nowadays the first duty of improving survival is to elucidate further the pathogenesis of adult ALL, to find new molecular targets and to better the evaluation system for prognosis. MSI2-NOTCH1pathway genes, mainly including MSI2, NUMB, NOTCH1, c-MYC and HES1, take part in various physiological functions such as embryonic development, self-renewal of stem cells and cellular differentiation. Some researches showed that mutations and abnormal expressions of these genes were closely associated with hematological malignancies, but there were no systematical studies on the association between these genes' expression levels and prognosis of adult patients with ALL. The balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs) can affect chromatin structure, which regulates the transcription of many important genes. HDACs abnormalities are involved in the pathogenesis of various kinds of tumors including leukemia. It is being a research focus that histone deacetylase inhibitors (HDACis) such as valproic acid (VPA) are to be used for treatment of different malignancies. In some tumor cells, VPA can inhibit cell growth by activating NOTCH1signaling. On the contrary, VPA can down-regulate NOTCH1expression to suppress other tumors. However, the role of MSI2-NOTCH1pathway in molecular mechanisms of VPA suppressing ALL cells has not been decribed. Hence, our study were divided into two parts, which explored the clinical significance of MSI2-NOTCH1pathway genes' expression in adult ALL and the pathway role in inhibition of VPA on ALL cells.
Part I:Study on expressions of MSI2-NOTCH1pathway genes in adult acute lymphoblastic leukemia and its clinical significance
Object:
The aim of this part was to discuss the association between expression levels of MSI2-NOTCH1pathway genes and prognosis of adult patients with acute lymphoblastic leukemia (ALL).
Methods:
Expression levels of MSI2、NUMB、NOTCH1、c-MYC and HES1in bone marrow mononuclear cells of144adult ALL patients and healthy controls were measured by real-time PCR. Expression differences of these genes between ALL patients and healthy controls as well as between B-ALL patients and T-ALL patients were observed. Several genes whose expressions were associated with overall survival (OS), event free survival (EFS) or relapse free survival (RFS) of adult ALL patients were screened out, correlations between their expression levels and other genes in this pathway as well as other clinical and laboratory factors were analyzed and changes of their expression levels at diagnosis and at complete remission were evaluated. After these genes' expressions were down-regulated by small interfering RNA (siRNA), cell growth, colony formation and apoptosis were observed. At the same time, expression levels of these genes which were down-regulated and other genes in MSI2-NOTCH1pathway were measured by real-time PCR and western blot, and then correlation among them were analyzed.
Result:
(1) Compared with healthy control, adult ALL patients harbored higher MSI2expression level (p<0.001) and lower NUMB and NOTCH1expression levels (both p <0.001respectively). However, there were no differences for c-MYC and HES1in both groups (p=0.645and p=0.108respectively).(2) Expression levels of NOTCH1and HES1in B-ALL patients were significantly lower than those in T-ALL patients (p=0.007and p=0.002respectively), but there were no obvious differences for MSI2, NUMB and NOTCHl in both groups (all p>0.05).(3) After MSI2-NOTCH1genes were screened out by Kaplan-Meier method, MSI2expression level was closely correlated with prognosis of ALL patients (p for OS was0.002and p for EFS was0.002).(4)In adult ALL patients, median OS, EFS and RFS of higher MSI2expression group were7.30months,5.90months and5.50months respectively, shorter than those of lower MSI2expression group (14.37months,9.26months and9.27months). After age, white cells count (WBC), t(9;22)/BCR-ABL and IK6adjusted by Backward LR Cox mode, median OS, EFS and RFS of higher MSI2expression group were significantly shorter than those of lower MSI2expression group (p was0.001,<0.001and0.043respectively).(5) In adult B-ALL patients, MSI2expression level was not correlated with age, sex, WBC, t(9;22)/BCR-ABL, MLL rearrangement and IK6, but higher MSI2expression group had higher rate of other adverse karyotypes including complex karyotype, near triploidy (60-78chromosomes), and del(9p)(n=5,17.3%) than lower MSI2expression group (n=3,3.4%, p=0.019).(6) In10paired samples, MSI2expression level at complete remission was obviously lower than that at diagnosis (p=0.007).(7) In healthy control subjects, MSI2expression was positively correlated with NUMB, NOTCH1, c-MYC and HES1(p was <0.001,<0.001,0.027and0.003respectively). However, in B-ALL or T-ALL patients, MSI2expression was positively correlated with NUMB or NOTCH1(all p<0.05) but not with c-MYC or HES1.(8) After MSI2expression in THP-1cells was down-regulated for24hours, cell viability of siRNA MSI2group was51.39±7.92%, obviously lower than that of negative control group (100%, p=0.005). After9days, cell colony count of siRNA MSI2group was7.50±1.53, also lower than that of negative control group (35.75±7.46, p<0.001). In addition, apoptotic rates of siRNA MSI2group at24and48hours were significantly higher than those of negative control group (p=0.008and p=0.001respectively). Accordingly, activations of Caspase-3and Parp were observed in siRNA MSI2group.(9) After MSI2expression was down-regulated for24or48hours, NUMB and NOTCH1at mRNA level didn't change (all p>0.05).
Conclusion:
(1) Of MSI2-NOTCH1pathway genes, higher expression level of MSI2is an adverse factor for prognosis of adult ALL patients and is an independently adverse factor for prognosis of adult B-ALL patients.(2) After MSI2expression in THP-1cells is down-regulated, cell viability decreases and apoptosis increases.(3) Different from normal cells, MSI2expression in ALL cells increased can not activate NOTCH1signaling.
Part II Study on the role of MSI2-NOTCH1pathway in inhibition of valproic acid on acute lymphoblastic leukemia cells
Object:
The aim of this part was to explore the role of MSI2-NOTCH1pathway in molecular mechanisms of valproic acid (VPA) suppressing acute lymphoblastic leukemia (ALL) cells.
Methods:
Cell growth, cell cycle and apoptosis of T-ALL cell lines including Jurkat, MOLT4and CEM and B-ALL cell line NALM6treated by VPA were examined by MTT, PI staining and flow cytometry. After Jurkat. MOLT4, CEM and NALM6cells were treated by VPA at0.8,1.6,2.4and3.2mM for24hours, expression levels of MSI2-NOTCH1pathway genes were measured by real-time PCR and Western blot. MTT, PI staining and Annexin V/PI staining were used to detect cell growth, cell cycle and apoptosis of Jurkat and CEM cells exposure to y-secretase inhibitor DAPT and/or VPA. At the same time, apoptotic-related proteins and MSI2-NOTCH1pathway proteins were measured by Western blot. After NOTCH signaling were activated by NOTCH ligand--Jagged-1, cell viabilities of Jurkat were treated by1.6、2.4、3.2or4.0mM VPA for24hours was monitored. In addition, in order to investigate the role of c-MYC in molecular mechanisms of valproic acid (VPA) suppressing ALL cells,60uM10058-F4plus VPA at different concentration were used to treat Jurkat and CEM cells and then cell growth, and apoptotic-related proteins were evaluated.
Results:
(1) MTT showed that a dose-and time-depended growth inhibition of Jurkat、MOLT4、 CEM and NALM6cells treated by VPA (0.2to12.8mM) for24and48hours was observed and their IC50values for24hours were5.37、7.02、4.69and7.56mM respectively. G0/G1ratios of NALM6、Jurkat、 MOLT4and CEM were63.27±2.75%、60.94±3.28%、53.50±2.27%and73.95±1.77%respectively after exposure to VPA (1.6mM), obviously higher than those of their controls (49.56±2.63%、43.33±1.76%.43.46±2.01%and61.39±3.58%). Apoptotic rates of Jurkat、MOLT4、CEM and NALM6cells treated by VPA at24hours increased in a dose-depended manner, accompanied with activation of BIM、Caspase-8、Caspase-9、Caspase-3and Parp.(2) Western blot showed that, in Jurkat、MOLT4、CEM and NALM6cells treated by VPA at experimental concentrations for24hours, protein level of MSI2did not vary, protein levels of NUMB, p27and non-phosphorylated RB increased and protein levels of c-MYC、CDK4、CDK6and phosphorylated RB decreased. Meantime, protein levels of NOTCH1of Jurkat、MOLT4and CEM cells were down-regulated notably, but that of NALM6cells was not affected. Protein levels of ICN1of Jurkat and CEM cells also decreased notably, but those of MOLT4and NALM6cells were undetectable. Real-time PCR showed that expression changes of NOTCH1mRNA and c-MYC mRNA were in accord with their proteins. Moreover, protein levels of NOTCH1、ICN1and c-MYC were down-regulated in Jurkat cells treated by VPA (0.8mM) for6,12,24and48hours or treated by SAHA for24hours.(3) DAPT increased growth inhibition of VPA at different concentrations on Jurkat and CEM cells (p=0.004and p<0.001respectively), but it could not increase further G0/G1arrest and activation of Caspase-3, Parp and LC3.(4) After Jagged-1activating NOTCH signaling of Jurkat cells, growth inhibition rates of the Jagged-1groups treated by VPA at different concentrations for24hours were significantly lower than those of the IgG groups treated by VPA at corresponding concentrations (p=0.019).(5) MTT results showed that growth inhibition rates of Jurkat and CEM cells treated by c-MYC inhibitors10058-F4combined with VPA at different concentrations were obviously higher than those of corresponding VPA groups (p=0.012and p=0.007respectively). Apoptotic rates of10058-F4pus VPA groups were higher than those of corresponding VPA groups (p=0.038and p=0.037respectively). Besides,10058-F4could increase further activation of Caspase-3and Parp in Jurkat and CEM cells treated by VPA (0.8mM,1.6mM).
Conclusions:
(1) VPA induces apoptosis and G0/G1arrest of Jurkat, MOLT4、CEM and NALM6cells to inhibit cell growth.
(2) VPA inhibits growth of Jurkat、MOLT4、CEM and NALM6cells through down-regulating c-MYC expression.
(3) Moreover, VPA also down-regulates NOTCH1mRNA and then inhibits NOTCH1signaling to suppress growth of Jurkat and CEM cells.
成人急性淋巴细胞白血病(acute lymphoblastic leukemia, ALL)是一组在临床和生物学上存在很大异质性的恶性肿瘤,其发病机制尚不清楚。尽管随着科学技术不断提高,成人ALL诱导缓解率已经有了很大提高,但其长期生存仍不尽人意。因而,进一步阐明成人ALL发病机制、寻找有效分子靶点以及完善其临床预后评价体系是当前提高治愈率的首要任务。MSI2-NOTCH1通路基因包括MSI2(Musashi-2)、NUMB、NOTCH1、c-MYC和HES1等基因,参与胚胎发育、干细胞自我更新、组织细胞分化等多种生理功能。一些研究显示,这些基因突变或异常表达与多种血液肿瘤发生或进展有密切的关系,但系统地分析这些基因表达水平与成人ALL患者预后关系的研究尚未见报道。组蛋白乙酰化酶和去乙酰化酶的动态平衡直接影响染色质的结构,调节很多基因的转录。组蛋白去乙酰化酶异常参与包括白血病在内多种肿瘤的发病机制,丙戊酸钠(valproic acid, VPA)等组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACIs)已成为肿瘤治疗一个热点。在一些肿瘤中,VPA能激活NOTCH1通路而抑制细胞生长；而另一些肿瘤中,VPA却下调NOTCH1表达水平。然而,MSI2-NOTCH1通路在VPA抑制ALL细胞生长分子机制中的作用仍不明了。为此,本研究分成两个部分分别阐述MSI2-NOTCH1通路基因在成人ALL中表达的临床意义和该通路基因在VPA抑制ALL细胞生长分子机制中的作用。
第一部分：MSI2-NOTCH1通路基因在成人急性淋巴细胞白血病中表达及其临床意义研究
目的：
探讨MSI2-NOTCH1通路基因表达水平与成人急性淋巴细胞白血病(ALL)患者预后的关系。
方法：
用实时定量PCR方法检测144例初发成人ALL患者骨髓单个核细胞和正常对照中的MSI2、NUMB、NOTCH1、c-MYC和HES1基因表达水平,比较这些基因在ALL和正常对照之间以及不同ALL亚型之间表达差别；筛选出与ALL患者的总生存(overall survival, OS),无事件生存(event free survival, EFS)或无复发生存(relapse free survival, RFS)密切相关的基因,并分析该基因表达水平与其他临床和实验室指标之间的关系；动态分析该基因表达水平在初发时和完全缓解时变化；比较该基因表达与其他MSI2-NOTCH1通路基因之间的关系；用siRNA (small interfering RNA)干扰方法下调该基因,用MTT法、集落培养、Annexin V/PI双染色法观察对THP-1细胞生长和凋亡影响,用定量PCR和western blot检测MSI2、NUMB和NOTCH1表达并分析它们之间的关系。
结果：
(1)与正常对照相比,ALL患者中的MSI2表达水平明显升高(p<0.001),而NUMB和NOTCH1明显减低(p值均小于0.001),两组的c-MYC和HES1基因表达水平无明显差别(p值分别为0.645和0.108)。(2) B-ALL患者的NOTCH1和HES1表达水平明显低于T-ALL患者(p值分别为0.007和0.002),但两组的MSI2、NUMB和c-MYC表达水平没有明显差别(p值均大于0.05)。(3)用Kaplan-Meier分析筛选后,在MSI2-NOTCH1通路基因中,MSI2表达水平与ALL患者预后密切相关(OS和EFS的p值均为0.002)。(4)在成人B-ALL患者中,MSI2高表达组的中位OS、EFS和RFS分别为7.30月、5.90月和5.50月,明显短于MSI2低表达组(分别为14.37月、9.26月和9.27月,p值分别为0.007、0.002和0.179)；用Backward LR Cox模型纠正白细胞数、t(9;22)/BCR-ABL和IK6等因素后,MSI2高表达组的生存仍明显差于低表达组,两组OS、EFS和RFS的p值分别为0.001、<0.001和0.043。(5)在成人B-ALL患者中,MSI2表达水平与年龄、性别、白细胞计数、t(9;22)/BCR-ABL、MLL重排和IKZF1基因IK6变异体没有明显相关性；但MSI2高表达组中复杂异常、近3倍体和9p-等少见不良核型率(n=5,17.3%)高于MSI2低表达组(n=3,3.4%,p=0.019)；(6)在10例配对标本中,与初发时相比,完全缓解时MSI2表达水平明显减低(p=0.007)。(7)在正常对照中,MSI2与NUMB、NOTCH1、c-MYC和HES1表达水平呈正相关(p值分别为<0.001、<0.001、0.027和0.003)；在B-ALL和T-ALL患者中,MSI2与NUMB、NOTCH1表达水平呈正相关(p值均小于0.05),但与c-MYC和HES1表达水平没有明显相关性(p值均大于0.05)。(8)沉默THP-1细胞MSI2基因24小时后,小干扰组细胞活力为51.39±7.92%,明显低于阴性对照组(100%,p=0.005)；培养9天后,小干扰组细胞集落数为7.50±1.53,明显低于阴性对照组(35.75±7.46,p<0.001)；小干扰组24和48小时凋亡率均明显高于阴性对照组(p值分别为0.008和0.001),并伴随Caspase-3和Parp剪切增加。(9)小干扰THP-1细胞MSI224和48小时,与阴性对照相比,NUMB和NOTCH1mRNA表达没有明显差别(p值均大于0.05)。
结论：
(1)在MSI2-NOTCH1通路基因中,MSI2高表达是成人ALL患者预后不良因素之一,是成人B-ALL患者预后不良独立危险因素之一。(2)下调MSI2表达水平能减低白血病细胞活力、导致细胞凋亡增加。(3)与正常细胞不同,ALL细胞中的MSI2表达水平增高不能激活NOTCH1信号。
第二部分：丙戊酸钠对急性淋巴细胞白血病的MSI2-NOTCH1通路影响研究
目的：
探讨MSI2-NOTCH1通路基因在组蛋白去乙酰化酶抑制剂丙戊酸钠(VPA)抑制急性淋巴细胞白血病(ALL)生长分子机制中的作用。
方法：
用MTT法、流式细胞术检测不同浓度VPA对T-ALL细胞株Jurkat、MOLT4和CEM细胞和B-ALL细胞株NALM6细胞生长、细胞周期和凋亡的影响；0.8、1.6、2.4和3.2mM浓度的VPA作用NALM6、Jurkat、MOLT4和CEM细胞24小时,定量PCR和Western blot检测凋亡相关蛋白、MSI2-NOTCH1通路基因及其下游基因表达变化。用MTT法、流式细胞术和Western blot观察γ-分泌酶抑制剂DAPT联合VPA作用Jurkat和CEM细胞后对其细胞生长、周期、凋亡和凋亡相关蛋白以及NOTCH1通路蛋白影响。NOTCH配体Jagged-1激活NOTCH信号24小时后,MTT法检测其对1.6、2.4、3.2和4.0mM浓度的VPA抑制Jurkat细胞生长的影响；60uM10058-F4联合不同浓度VPA作用Jurkat和CEM细胞后,用MTT法、Annexin V/PI和Western blot观察细胞生长、凋亡及凋亡相关蛋白变化。
结果：
(1)用0.2-12.8mM浓度VPA作用Jurkat、MOLT4、CEM和NALM6细胞,24和48小时4株细胞生长均受到不同程度抑制,其24小时IC50分别为5.37、7.02、4.69和7.56mM;1.6mM VPA作用Jurkat、MOLT4、CEM和NALM6细胞24小时,其G0/G1细胞比例分别为63.27±2.75%、60.94±3.28%、53.50±2.27%和73.95±1.77%,均明显高于对照组(49.56±2.63%、43.33±1.76%、43.46±2.01%和61.39±3.58%)；实验浓度VPA作用Jurkat、MOLT4、CEM和NALM6细胞24小时,其凋亡率呈现浓度依赖性增加,伴随BIM、Caspase-8、Caspase-9、Caspase-3和Parp不同程度激活；(2)实验浓度VPA作用Jurkat、MOLT4、CEM和NALM6细胞24小时,与对照组相比,MSI2变化不明显；NUMB、p27和非磷酸化RB均出现不同程度上调；c-MYC.CDK4.CDK6和磷酸化RB均出现下调；在Jurkat、 MOLT4和CEM细胞中,NOTCH1出现明显下调,但在NALM6细胞中NOTCH1没有变化；ICN1在Jurkat和CEM细胞中明显下调,在MOLT4和NALM6细胞中没有检测到。定量PCR检测NOTCH1和c-MYC mRNA表达水平,其变化与蛋白水平一致。以0.8mM VPA作用Jurkat细胞6h、12h、24h和2d以及用实验浓度SAHA作用Jurkat细胞,均能观察到NOTCH1、ICN1和c-MYC蛋白下调。(3)15μM DAPT联合不同浓度VPA作用Jurkat和CEM细胞24小时,DAPT处理后不同实验浓度VPA组生长抑制率均明显高于DMSO处理的相应VPA组,p值分别为0.004和0.001。但DAPT组不能增加VPA对Jurkat和CEM细胞的G0/G1阻滞、Caspase-3、Parp和LC3的激活。(4)用Jagged-1激活Jurkat细胞NOTCH信号,Jagged-1处理后不同实验浓度VPA组24小时抑制率均明显低于IgG处理的相应VPA组,p=0.019。(5)用c-MYC抑制剂10058-F4处理Jurkat和CEM细胞后,加不同实验浓度VPA作用24小时,MTT法检测显示10058-F4处理后不同实验浓度VPA组的生长抑制率均明显高于相应VPA组,p值分别为0.012和0.007; Annexin V/PI双染法检测显示,用10058-F4处理的不同实验浓度VPA组的细胞凋亡率均明显高于DMSO处理的相应VPA组,p值分别为0.038和0.037；在Jurkat和CEM细胞中,10058-F4能进一步增加0.8和1.6mM VPA对Parp和Caspase-3的剪切。
结论：
(1)VPA能通过诱导细胞凋亡和阻滞细胞周期而抑制ALL细胞生长；
(2)VPA能通过下调c-MYC表达实现对ALL细胞生长抑制。
(3)VPA还能通过下调NOTCH1转录水平,抑制NOTCH1信号实现对Jurkat和CEM细胞生长抑制。
Backgroud:
Adult acute lymphoblastic leukemia (ALL) is a group of malignant tumors with marked clinical and biological heterogeneity and its pathogenesis remains unclear. With science and technology development, the induction remission rate in adult ALL has been greatly improved, but its long survival remains poor. Thus, nowadays the first duty of improving survival is to elucidate further the pathogenesis of adult ALL, to find new molecular targets and to better the evaluation system for prognosis. MSI2-NOTCH1pathway genes, mainly including MSI2, NUMB, NOTCH1, c-MYC and HES1, take part in various physiological functions such as embryonic development, self-renewal of stem cells and cellular differentiation. Some researches showed that mutations and abnormal expressions of these genes were closely associated with hematological malignancies, but there were no systematical studies on the association between these genes' expression levels and prognosis of adult patients with ALL. The balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs) can affect chromatin structure, which regulates the transcription of many important genes. HDACs abnormalities are involved in the pathogenesis of various kinds of tumors including leukemia. It is being a research focus that histone deacetylase inhibitors (HDACis) such as valproic acid (VPA) are to be used for treatment of different malignancies. In some tumor cells, VPA can inhibit cell growth by activating NOTCH1signaling. On the contrary, VPA can down-regulate NOTCH1expression to suppress other tumors. However, the role of MSI2-NOTCH1pathway in molecular mechanisms of VPA suppressing ALL cells has not been decribed. Hence, our study were divided into two parts, which explored the clinical significance of MSI2-NOTCH1pathway genes' expression in adult ALL and the pathway role in inhibition of VPA on ALL cells.
Part I:Study on expressions of MSI2-NOTCH1pathway genes in adult acute lymphoblastic leukemia and its clinical significance
Object:
The aim of this part was to discuss the association between expression levels of MSI2-NOTCH1pathway genes and prognosis of adult patients with acute lymphoblastic leukemia (ALL).
Methods:
Expression levels of MSI2、NUMB、NOTCH1、c-MYC and HES1in bone marrow mononuclear cells of144adult ALL patients and healthy controls were measured by real-time PCR. Expression differences of these genes between ALL patients and healthy controls as well as between B-ALL patients and T-ALL patients were observed. Several genes whose expressions were associated with overall survival (OS), event free survival (EFS) or relapse free survival (RFS) of adult ALL patients were screened out, correlations between their expression levels and other genes in this pathway as well as other clinical and laboratory factors were analyzed and changes of their expression levels at diagnosis and at complete remission were evaluated. After these genes' expressions were down-regulated by small interfering RNA (siRNA), cell growth, colony formation and apoptosis were observed. At the same time, expression levels of these genes which were down-regulated and other genes in MSI2-NOTCH1pathway were measured by real-time PCR and western blot, and then correlation among them were analyzed.
Result:
(1) Compared with healthy control, adult ALL patients harbored higher MSI2expression level (p<0.001) and lower NUMB and NOTCH1expression levels (both p <0.001respectively). However, there were no differences for c-MYC and HES1in both groups (p=0.645and p=0.108respectively).(2) Expression levels of NOTCH1and HES1in B-ALL patients were significantly lower than those in T-ALL patients (p=0.007and p=0.002respectively), but there were no obvious differences for MSI2, NUMB and NOTCHl in both groups (all p>0.05).(3) After MSI2-NOTCH1genes were screened out by Kaplan-Meier method, MSI2expression level was closely correlated with prognosis of ALL patients (p for OS was0.002and p for EFS was0.002).(4)In adult ALL patients, median OS, EFS and RFS of higher MSI2expression group were7.30months,5.90months and5.50months respectively, shorter than those of lower MSI2expression group (14.37months,9.26months and9.27months). After age, white cells count (WBC), t(9;22)/BCR-ABL and IK6adjusted by Backward LR Cox mode, median OS, EFS and RFS of higher MSI2expression group were significantly shorter than those of lower MSI2expression group (p was0.001,<0.001and0.043respectively).(5) In adult B-ALL patients, MSI2expression level was not correlated with age, sex, WBC, t(9;22)/BCR-ABL, MLL rearrangement and IK6, but higher MSI2expression group had higher rate of other adverse karyotypes including complex karyotype, near triploidy (60-78chromosomes), and del(9p)(n=5,17.3%) than lower MSI2expression group (n=3,3.4%, p=0.019).(6) In10paired samples, MSI2expression level at complete remission was obviously lower than that at diagnosis (p=0.007).(7) In healthy control subjects, MSI2expression was positively correlated with NUMB, NOTCH1, c-MYC and HES1(p was <0.001,<0.001,0.027and0.003respectively). However, in B-ALL or T-ALL patients, MSI2expression was positively correlated with NUMB or NOTCH1(all p<0.05) but not with c-MYC or HES1.(8) After MSI2expression in THP-1cells was down-regulated for24hours, cell viability of siRNA MSI2group was51.39±7.92%, obviously lower than that of negative control group (100%, p=0.005). After9days, cell colony count of siRNA MSI2group was7.50±1.53, also lower than that of negative control group (35.75±7.46, p<0.001). In addition, apoptotic rates of siRNA MSI2group at24and48hours were significantly higher than those of negative control group (p=0.008and p=0.001respectively). Accordingly, activations of Caspase-3and Parp were observed in siRNA MSI2group.(9) After MSI2expression was down-regulated for24or48hours, NUMB and NOTCH1at mRNA level didn't change (all p>0.05).
Conclusion:
(1) Of MSI2-NOTCH1pathway genes, higher expression level of MSI2is an adverse factor for prognosis of adult ALL patients and is an independently adverse factor for prognosis of adult B-ALL patients.(2) After MSI2expression in THP-1cells is down-regulated, cell viability decreases and apoptosis increases.(3) Different from normal cells, MSI2expression in ALL cells increased can not activate NOTCH1signaling.
Part II Study on the role of MSI2-NOTCH1pathway in inhibition of valproic acid on acute lymphoblastic leukemia cells
Object:
The aim of this part was to explore the role of MSI2-NOTCH1pathway in molecular mechanisms of valproic acid (VPA) suppressing acute lymphoblastic leukemia (ALL) cells.
Methods:
Cell growth, cell cycle and apoptosis of T-ALL cell lines including Jurkat, MOLT4and CEM and B-ALL cell line NALM6treated by VPA were examined by MTT, PI staining and flow cytometry. After Jurkat. MOLT4, CEM and NALM6cells were treated by VPA at0.8,1.6,2.4and3.2mM for24hours, expression levels of MSI2-NOTCH1pathway genes were measured by real-time PCR and Western blot. MTT, PI staining and Annexin V/PI staining were used to detect cell growth, cell cycle and apoptosis of Jurkat and CEM cells exposure to y-secretase inhibitor DAPT and/or VPA. At the same time, apoptotic-related proteins and MSI2-NOTCH1pathway proteins were measured by Western blot. After NOTCH signaling were activated by NOTCH ligand--Jagged-1, cell viabilities of Jurkat were treated by1.6、2.4、3.2or4.0mM VPA for24hours was monitored. In addition, in order to investigate the role of c-MYC in molecular mechanisms of valproic acid (VPA) suppressing ALL cells,60uM10058-F4plus VPA at different concentration were used to treat Jurkat and CEM cells and then cell growth, and apoptotic-related proteins were evaluated.
Results:
(1) MTT showed that a dose-and time-depended growth inhibition of Jurkat、MOLT4、 CEM and NALM6cells treated by VPA (0.2to12.8mM) for24and48hours was observed and their IC50values for24hours were5.37、7.02、4.69and7.56mM respectively. G0/G1ratios of NALM6、Jurkat、 MOLT4and CEM were63.27±2.75%、60.94±3.28%、53.50±2.27%and73.95±1.77%respectively after exposure to VPA (1.6mM), obviously higher than those of their controls (49.56±2.63%、43.33±1.76%.43.46±2.01%and61.39±3.58%). Apoptotic rates of Jurkat、MOLT4、CEM and NALM6cells treated by VPA at24hours increased in a dose-depended manner, accompanied with activation of BIM、Caspase-8、Caspase-9、Caspase-3and Parp.(2) Western blot showed that, in Jurkat、MOLT4、CEM and NALM6cells treated by VPA at experimental concentrations for24hours, protein level of MSI2did not vary, protein levels of NUMB, p27and non-phosphorylated RB increased and protein levels of c-MYC、CDK4、CDK6and phosphorylated RB decreased. Meantime, protein levels of NOTCH1of Jurkat、MOLT4and CEM cells were down-regulated notably, but that of NALM6cells was not affected. Protein levels of ICN1of Jurkat and CEM cells also decreased notably, but those of MOLT4and NALM6cells were undetectable. Real-time PCR showed that expression changes of NOTCH1mRNA and c-MYC mRNA were in accord with their proteins. Moreover, protein levels of NOTCH1、ICN1and c-MYC were down-regulated in Jurkat cells treated by VPA (0.8mM) for6,12,24and48hours or treated by SAHA for24hours.(3) DAPT increased growth inhibition of VPA at different concentrations on Jurkat and CEM cells (p=0.004and p<0.001respectively), but it could not increase further G0/G1arrest and activation of Caspase-3, Parp and LC3.(4) After Jagged-1activating NOTCH signaling of Jurkat cells, growth inhibition rates of the Jagged-1groups treated by VPA at different concentrations for24hours were significantly lower than those of the IgG groups treated by VPA at corresponding concentrations (p=0.019).(5) MTT results showed that growth inhibition rates of Jurkat and CEM cells treated by c-MYC inhibitors10058-F4combined with VPA at different concentrations were obviously higher than those of corresponding VPA groups (p=0.012and p=0.007respectively). Apoptotic rates of10058-F4pus VPA groups were higher than those of corresponding VPA groups (p=0.038and p=0.037respectively). Besides,10058-F4could increase further activation of Caspase-3and Parp in Jurkat and CEM cells treated by VPA (0.8mM,1.6mM).
Conclusions:
(1) VPA induces apoptosis and G0/G1arrest of Jurkat, MOLT4、CEM and NALM6cells to inhibit cell growth.
(2) VPA inhibits growth of Jurkat、MOLT4、CEM and NALM6cells through down-regulating c-MYC expression.
(3) Moreover, VPA also down-regulates NOTCH1mRNA and then inhibits NOTCH1signaling to suppress growth of Jurkat and CEM cells.
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