Development of the method to surmise the prognosis of acute myeloblastic leukemia patients by analyzing the expression of Notch protein

建立通过分析Notch蛋白表达来推测急性髓细胞白血病患者预后的方法

• 批准号: 13672415
• 负责人: TOHDA Shuji
• 金额: $ 1.02万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672415/
• 关键词: acute myeloblastic leukemia; Notch; Jagged; Delta; 白血病

The self-renewal and differentiation of hematopoietic progenitors are regulated by the interaction between Notch receptors and Notch ligands. Since acute myeloblastic leukemia (AML) originates from dysregulated hematopoietic progenitors, we thought that some abnormalities in the Notch system might be involved in the abnormal proliferation of AML cells. Furthermore, we thought that the expression of Notch protein might be one of the prognostic factors of the patients. Firstly, we found that most of the AML cell lines and half of the primary AML cells from patients expressed Notch-1 protein. Some samples showed a fragment which appeared to be a constitutively active form or an aberrant sized fragment. Other samples expressed the Notch ligand protein such as Jagged 1. Secondly, we established a novel human AML cell line, TMD7, of which growth was stimulated by Notch ligands. Thirdly, we examined the effects of recombinant Notch ligand proteins on in vitro growth of AML cells. For TMD7 cells, the Notch ligand promoted the short-term growth, however, suppressed the self-renewal capacity and long-term growth. For another cell line, Notch ligand protein suppressed the growth and self-renewal capacity while inducing differentiation into macrophage-like cells. We additionally found that Notch ligands needed to be immobilized on culture wells to affect the cells. At present, we are examining the effects of the Notch ligands on the growth of primary AML cells from patients. Until now, we have not found the clear relationship between the prognosis of the patients and the expression of Notch proteins.

造血祖细胞的自我更新和分化受Notch受体和Notch配体的相互作用调控。由于急性髓母细胞白血病（AML）起源于造血祖细胞失调，我们认为Notch系统的某些异常可能与AML细胞的异常增殖有关。此外，我们认为Notch蛋白的表达可能是影响患者预后的因素之一。首先，我们发现大多数AML细胞系和一半患者的原代AML细胞表达Notch-1蛋白。一些样品显示一个片段，似乎是一个组成活性形式或一个异常大小的片段。其他样品表达Notch配体蛋白，如Jagged 1。其次，我们建立了一种新的人类AML细胞系TMD7，它的生长受到Notch配体的刺激。第三，我们检测了重组Notch配体蛋白对AML细胞体外生长的影响。对于TMD7细胞，Notch配体促进了细胞的短期生长，但抑制了细胞的自我更新能力和长期生长。对于另一种细胞系，Notch配体蛋白抑制生长和自我更新能力，诱导分化为巨噬细胞样细胞。我们还发现Notch配体需要固定在培养孔上才能影响细胞。目前，我们正在研究Notch配体对患者原发性AML细胞生长的影响。到目前为止，我们还没有发现患者预后与Notch蛋白表达之间的明确关系。

项目成果

Tohda S: "Expression of Notch I and jagged I proteins in acutemyeloid leukemia cells"Leukemia and Lymphoma. 42・3. 467-472 (2001)

Tohda S：“Notch I 和锯齿状 I 蛋白在急性髓性白血病细胞中的表达”《白血病和淋巴瘤》42·3（2001）。

Tohda S: "A novel cell line derived from de novo acute myeloblastic lenkaemia with trilineage myelodysplasia which proliferates in response to a Notch ligand, Pelto-1 protein"British Journal of Haematulogy. 117. 373-378 (2002)

Tohda S：“一种源自患有三系骨髓增生异常的新发急性成髓细胞性白血病的新型细胞系，该细胞系响应 Notch 配体 Pelto-1 蛋白而增殖”，《英国血液学杂志》。

Tohda S: "Human herpesvirus 8 DNA in HIV-negative Japanese patients with multicentric Casfleman's disease and related diseases"International Journal of Molecular Medicine. 8. 549-551 (2001)

Tohda S：“患有多中心卡斯夫尔曼病和相关疾病的 HIV 阴性日本患者中的人类疱疹病毒 8 DNA”《国际分子医学杂志》。

Tohda S: "A novel cell line derived from de nove acute myelohlastic Leukaemia with trilineage myelodysphasid which prolifevates in response to a Notch ligand, Delta 1 protein"British Journal of Haematology. (in press).

Tohda S：“一种源自新发急性髓系白血病的新型细胞系，具有三系骨髓相间症，其对 Notch 配体 Delta 1 蛋白作出反应而增殖”，《英国血液学杂志》。

Tohda S: "A novel cell line derived from de novo acute myeloblastic leukaemia with trilineage myelodysplasia which proliferates in response to a Notch ligand, Delta-1 protein"British Journal of Haematology. 117. 373-378 (2002)

Tohda S：“一种源自具有三系骨髓增生异常的新发急性成髓细胞白血病的新型细胞系，其响应 Notch 配体 Delta-1 蛋白而增殖”《英国血液学杂志》。