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The method to surmise the prognosis of leukemia patients by analyzing the function of Notch protein

分析Notch蛋白功能推测白血病患者预后的方法

基本信息

批准号：
16590446
负责人：
TOHDA Shuji
金额：
$ 1.22万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590446/
关键词：
Notch leukemia Jagged Delta

项目摘要

Notch signaling regulates the self-renewal and differentiation of hematopoietic progenitors. Since acute myeloblastic leukemia (AML) originates from dysregulated hematopoietic progenitors, the Notch system may be involved in the abnormal growth. We previously reported that AML cells express Notch proteins. In this study, we examined the effects of Notch ligands on the growth and differentiation of primary AML cells. AML cells were cultured in wells coated with the ligands or control IgG. The short-term growth, self-renewal capacity and differentiation were evaluated. The ligand stimulation caused three types of response in the short-term growth, namely, promotion, suppression or no significant effect. The self-renewal capacity was suppressed or not significantly affected by the ligands. The ligand stimulation altered blast cells into macrophage-like cells in some samples. Thus, Notch activation caused by the ligand stimulation had diverse effects. The relationship between responsiveness of the cells and prognosis of the patients could not be clarified yet.Effects of Notch activation on retinoic acid (RA)-induced differentiation and apoptosis were investigated. Acute promyelocytic leukemia (APL) cells undergo neutrophilic differentiation and apoptosis by RA. Notch activation induced by the Notch ligands made part of RA-treated NB4 cells monocyte-like shaped and reduced the apoptosis. The ligands suppressed the RA-induced cleavage of caspase-8 and PARP, which may be a possible mechanism through which the ligands suppress the RA-induced apoptosis.The effect of the Notch ligands on drug-sensitivity of leukemia cells was examined. The drug-induced growth suppression was slightly reduced by the ligand stimulation in some cells. The ligand-coated culture-plates are more similar to the microenvironment in human bone marrow than ordinary plates. We will further examine the clinical usefulness of the drug-sensitivity test using the ligand-coated plates.

Notch信号调节造血祖细胞的自我更新和分化。由于急性髓母细胞白血病（AML）起源于造血祖细胞失调，Notch系统可能参与了其异常生长。我们之前报道过AML细胞表达Notch蛋白。在这项研究中，我们研究了Notch配体对原代AML细胞生长和分化的影响。AML细胞在涂有配体或对照IgG的孔中培养。对其短期生长、自我更新能力和分化进行了评价。配体刺激在短期生长中引起三种类型的反应，即促进、抑制或无显著作用。这些配体抑制或不显著影响细胞的自我更新能力。在一些样品中，配体刺激使原始细胞转变为巨噬细胞样细胞。因此，配体刺激引起的Notch激活具有多种作用。细胞的反应性与患者预后之间的关系尚不清楚。研究了Notch激活对维甲酸（RA）诱导的细胞分化和细胞凋亡的影响。RA诱导急性早幼粒细胞白血病（APL）细胞嗜中性分化和凋亡。Notch配体诱导的Notch激活使部分ra处理的NB4细胞呈单核细胞样形状，减少了细胞凋亡。这些配体抑制了ra诱导的caspase-8和PARP的裂解，这可能是其抑制ra诱导的细胞凋亡的机制之一。观察Notch配体对白血病细胞药物敏感性的影响。在某些细胞中，配体刺激可轻微减轻药物诱导的生长抑制作用。配体包被培养板比普通培养板更接近人骨髓微环境。我们将进一步研究使用配体包被板进行药物敏感性试验的临床用途。