CN1666780A - A method for degrading AML1-ETO fusion protein and reagents used - Google Patents
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Abstract
本发明是一种降解AML1－ETO融合蛋白的方法及所用的试剂。应用0.5～10μM浓度的冬凌草甲素处理Kasumi－1细胞，2～72小时后可引起AML1－ETO融合蛋白的降解。在转染了AML1－ETO融合基因的U937细胞，冬凌草甲素同样可降解AML1－ETO融合蛋白。本发明为开发具有t(8；21)染色体易位的白血病靶向治疗药物奠定了基础，同时为AML1－ETO融合蛋白的生物学功能研究提供了新的途径与试剂，还为拓宽冬凌草甲素的临床/实验研究用途提供了依据。The invention is a method for degrading AML1-ETO fusion protein and the reagent used. Treatment of Kasumi-1 cells with 0.5-10 μM concentration of oridonin can cause the degradation of AML1-ETO fusion protein after 2-72 hours. In U937 cells transfected with AML1-ETO fusion gene, Rubescensine A can also degrade AML1-ETO fusion protein. The present invention lays the foundation for the development of targeted therapy drugs for leukemia with t(8;21) chromosomal translocation, and at the same time provides a new approach and reagent for the study of the biological function of the AML1-ETO fusion protein, and also provides a new method for broadening the range of Rubescens japonicus The clinical/experimental research use of methadone provides a basis.
Description
技术领域technical field
本发明公开一种降解AML1-ETO融合蛋白的方法及所用试剂。The invention discloses a method for degrading AML1-ETO fusion protein and the reagent used.
背景技术Background technique
白血病的发生多与基因组的异常改变有关，某一种(或一些)异常分子可通过多种机制最终引起白血病细胞的恶性增殖、分化受阻、凋亡受抑制而导致疾病的发生。靶向降解这种(或这些)异常分子自然成为白血病治疗的一种策略，而且这种靶向疗法往往具有疗效高而毒副作用低的特点，是人类赖以征服白血病的有力工具。典型的例子是全反式维甲酸(ATRA)、三氧化二砷(ATO)通过降解PML-RARα融合蛋白诱导急性早幼粒细胞白血病(APL)白血病细胞的分化与凋亡，大大改善了APL患者的预后，使APL成为一种有希望被治愈的白血病。M2型急性髓性白血病(AML M2)占所有急性髓性白血病(AML)的25％，以具有t(8；21)染色体易位为特征，其形成的AML1-ETO融合蛋白是AML M2的发病原因。该病临床表现为发热、贫血、出血及粒细胞肉瘤等症状体征，而外周血中常有白细胞增高，红细胞、血小板减少。治疗上以阿糖胞苷、柔红霉素等化疗为主，而缺少特异针对AML1-ETO融合蛋白的有效治疗方法。开发靶向降解AML1-ETO融合蛋白并诱导t(8；21)白血病细胞凋亡/分化的药物，对进一步改善AML M2患者的临床疗效具有重要的意义。The occurrence of leukemia is mostly related to abnormal changes in the genome. A certain (or some) abnormal molecules can eventually cause malignant proliferation, differentiation blockage, and apoptosis inhibition of leukemia cells through various mechanisms, leading to the occurrence of the disease. Targeted degradation of this (or these) abnormal molecules has naturally become a strategy for leukemia treatment, and this targeted therapy often has the characteristics of high efficacy and low side effects, and is a powerful tool for human beings to conquer leukemia. A typical example is that all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) induce the differentiation and apoptosis of acute promyelocytic leukemia (APL) leukemia cells by degrading the PML-RARα fusion protein, which greatly improves the prognosis of APL patients. Make APL a kind of leukemia that has the hope of being cured. M2 acute myeloid leukemia (AML M2) accounts for 25% of all acute myeloid leukemia (AML), and is characterized by t(8;21) chromosome translocation, and the AML1-ETO fusion protein formed by it is the pathogenesis of AML M2 reason. The clinical manifestations of the disease are fever, anemia, hemorrhage, and granulocytic sarcoma, while the peripheral blood often has increased white blood cells, decreased red blood cells, and thrombocytopenia. The treatment is mainly based on chemotherapy such as cytarabine and daunorubicin, but there is a lack of effective treatment methods that specifically target the AML1-ETO fusion protein. The development of drugs that target the degradation of AML1-ETO fusion protein and induce apoptosis/differentiation of t(8;21) leukemia cells is of great significance for further improving the clinical efficacy of AML M2 patients.
发明内容Contents of the invention
本发明的目的在于提出一种降解AML1-ETO融合蛋白的方法。The purpose of the present invention is to propose a method for degrading AML1-ETO fusion protein.
本发明的另一目的在于提出一种降解AML1-ETO融合蛋白所用的试剂。Another object of the present invention is to provide a reagent for degrading AML1-ETO fusion protein.
本发明的技术特征是，采用0.5～10μM浓度的冬凌草甲素处理含有t(8；21)染色体易位的Kasumi-1细胞，2～72小时后可引起AML1-ETO融合蛋白的降解；用0.5～10μM浓度的冬凌草甲素处理转染过AML1-ETO融合基因的U937细胞2～72小时，也可引起AML1-ETO融合蛋白的降解。冬凌草甲素降解AML1-ETO融合蛋白的途径有两种，一是活化通过caspases，二是通过ubiquitin途径。The technical feature of the present invention is that treatment of Kasumi-1 cells containing t(8;21) chromosomal translocation with 0.5-10 μM concentration of oridonin can cause the degradation of AML1-ETO fusion protein after 2-72 hours; Treating the U937 cells transfected with the AML1-ETO fusion gene with 0.5-10 μM concentration of Rubescensin A for 2-72 hours can also cause the degradation of the AML1-ETO fusion protein. There are two pathways for Rubescensin A to degrade AML1-ETO fusion protein, one is activated through caspases, and the other is through ubiquitin pathway.
研究发现，冬凌草甲素对Kasumi-1、NB4、HL-60、U937、K562等白血病细胞均有增殖抑制作用，但对具有AML1-ETO融合蛋白的Kasumi-1细胞作用最为明显，IC50最低；且冬凌草甲素对BCR-ABL融合蛋白无降解作用，说明其对AML1-ETO融合蛋白的降解有一定的特异性。Studies have found that Rubescensine A has inhibitory effects on the proliferation of Kasumi-1, NB4, HL-60, U937, K562 and other leukemia cells, but the most obvious effect on Kasumi-1 cells with AML1-ETO fusion protein, IC 50 The lowest; and Rubescensin A has no degradation effect on BCR-ABL fusion protein, indicating that it has certain specificity to the degradation of AML1-ETO fusion protein.
以上发现为开发具有t(8；21)染色体易位的白血病的靶向疗法奠定了基础，也为研究AML1-ETO融合蛋白的生物学功能提供了新的途径与试剂。The above findings laid the foundation for the development of targeted therapy for leukemia with t(8;21) chromosome translocation, and also provided a new approach and reagent for studying the biological function of AML1-ETO fusion protein.
比较现有技术，本发明具有以下技术特点：Compared with the prior art, the present invention has the following technical characteristics:
1，提出一种降解AML1-ETO融合蛋白的方法和降解AML1-ETO融合蛋白所用的试剂，揭示了四环二萜类化合物新的生物学功能。为开发具有t(8；21)染色体易位的白血病的靶向治疗药物奠定了基础；为研究AML1-ETO融合蛋白的生物学功能提供了新的途径与试剂。1. Propose a method for degrading AML1-ETO fusion protein and the reagents used for degrading AML1-ETO fusion protein, revealing new biological functions of tetracyclic diterpenoids. It lays the foundation for the development of targeted therapeutic drugs for leukemia with t(8;21) chromosome translocation; it provides a new way and reagent for studying the biological function of AML1-ETO fusion protein.
2，发现了冬凌草甲素新的生物学效应。冬凌草甲素可降解AML1-ETO融合蛋白并诱导AML M2白血病细胞凋亡，加上其毒副作用低而且价格低廉，因此有较为广阔的临床应用前景。2. Discovered new biological effects of oridonin. Rubescensine A can degrade AML1-ETO fusion protein and induce apoptosis of AML M2 leukemia cells. In addition, it has low toxic and side effects and low price, so it has broad clinical application prospects.
附图说明Description of drawings
图1冬凌草甲素对AML1-ETO融合蛋白的降解作用Fig. 1 Degradation effect of oridonin on AML1-ETO fusion protein
图2冬凌草甲素对BCR-ABL融合蛋白的作用。示冬凌草甲素不能降解BCR-ABL融合蛋白，而ATO可对其进行降解。Fig. 2 The effect of oridonin on BCR-ABL fusion protein. It was shown that Rubescensin A could not degrade BCR-ABL fusion protein, but ATO could degrade it.
具体实施方式Detailed ways
I、我们用不同浓度的冬凌草甲素(0.5～5μM浓度)处理Kasumi-1细胞24、48小时后提取其蛋白质，进行Western印迹杂交，发现冬凌草甲素可将94kDa的AML1-ETO蛋白降解，降解片段大小分别为70kDa、25kDa左右(见图1)。(1为对照，2～4分别为0.5、2、5μM冬凌草甲素作用24小时后Kasumi-1细胞AML-ETO蛋白的变化，5～7为0.5、2、5μM冬凌草甲素处理48小时后Kasumi-1细胞AML-ETO蛋白的变化。上方箭头所示为AML1-ETO融合蛋白，中下方箭头所示为降解产物。)I. We treated Kasumi-1 cells with different concentrations of Rubescensin (0.5～5μM concentration) for 24 and 48 hours, extracted its protein, carried out Western blot hybridization, and found that Rubescensine A could convert 94kDa AML1-ETO The protein is degraded, and the sizes of the degraded fragments are about 70kDa and 25kDa respectively (see Figure 1). (1 is the control, 2 to 4 are the changes of AML-ETO protein in Kasumi-1 cells after 24 hours of 0.5, 2, and 5 μM oridonin respectively, and 5 to 7 are 0.5, 2, and 5 μM oridonin treatments Changes of AML-ETO protein in Kasumi-1 cells after 48 hours. The upper arrow shows the AML1-ETO fusion protein, and the lower middle arrow shows the degradation product.)
II、我们用免疫荧光的方法检测经冬凌草甲素处理后Kasumi-1细胞内AML1-ETO及ETO蛋白的分布情况，发现Kasumi-1细胞内AML1-ETO、ETO蛋白的表达明显降低。II. We used immunofluorescence to detect the distribution of AML1-ETO and ETO proteins in Kasumi-1 cells after treatment with oridonin, and found that the expressions of AML1-ETO and ETO proteins in Kasumi-1 cells were significantly reduced.
III、用冬凌草甲素处理转染过AML1-ETO融合基因的U937细胞，再提取其蛋白并进行Western印迹杂交试验，亦发现冬凌草甲素可降解AML1-ETO融合蛋白。III. U937 cells transfected with AML1-ETO fusion gene were treated with Rubescensin A, and then the protein was extracted and subjected to Western blot hybridization test. It was also found that Rubescensin A could degrade AML1-ETO fusion protein.
IV、我们比较了冬凌草甲素对Kasumi-1、NB4、HL-60、U937、K562等细胞的增殖抑制作用，发现冬凌草甲素对具AML1-ETO融合蛋白的Kasumi-1细胞作用最为明显，IC50最低(表1)。且冬凌草甲素对BCR-ABL融合蛋白无降解作用(图2)，说明其对AML1-ETO融合蛋白的降解有一定的特异性。IV. We compared the inhibitory effect of oridonin on Kasumi-1, NB4, HL-60, U937, K562 and other cells, and found that oridonin had the effect on Kasumi-1 cells with AML1-ETO fusion protein Most notably, the IC50 was the lowest (Table 1). And Rubescensin A has no degradative effect on BCR-ABL fusion protein (Figure 2), indicating that it has certain specificity to the degradation of AML1-ETO fusion protein.
表1 冬凌草甲素对不同白血病细胞的增殖抑制作用
V、我们用冬凌草甲素(0.5～5μM浓度)处理Kasumi-1细胞，发现其可诱导白血病细胞出现凋亡小体与DNA“梯形”条带，磷脂酰丝氨酸表化与末端脱氧核苷酰转移酶介导的原位凋亡检测阳性，细胞周期出现亚G1峰，这种效应呈剂量-时间依赖性。冬凌草甲素还可引起Kasumi-1细胞线粒体跨膜电位的崩解、caspases的活化及bcl-2癌蛋白表达下降等。对其它白血病细胞株如NB4、HL-60、K562、U937等细胞，冬凌草甲素也可诱导其凋亡，但所需浓度较高，在5～15μM间。V. We treated Kasumi-1 cells with Rubescensine A (0.5-5 μM concentration), and found that it can induce leukemia cells to appear apoptotic bodies and DNA "ladder" bands, phosphatidylserine surface and terminal deoxynucleosides In situ apoptosis mediated by acyltransferases was positive, and a sub-G1 peak of the cell cycle occurred, and this effect was dose-time dependent. Oridonin can also cause the disintegration of mitochondrial transmembrane potential, the activation of caspases and the decrease of bcl-2 oncoprotein expression in Kasumi-1 cells. For other leukemia cell lines such as NB4, HL-60, K562, U937 and other cells, oridonin can also induce apoptosis, but the required concentration is higher, between 5 and 15 μM.
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| CN (1) | CN1329083C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007051390A1 (en) * | 2005-11-07 | 2007-05-10 | Rui Jin Hospital Affiliated To Shanghai Second Medical University | The use of eriocalyxin b in the manufacture of medicaments for treating leukemia |
| WO2008022505A1 (en) * | 2006-08-18 | 2008-02-28 | Rui Jin Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine | Use of rubescensine a and derivatives thereof in pharmacy |
| WO2014048109A1 (en) * | 2012-09-29 | 2014-04-03 | 中山大学 | Reagent for targeting degradation of bcr-abl protein and use in preparation of philadelphia chromosome-positive tumor-curing medicine |
| WO2025087245A1 (en) * | 2023-10-23 | 2025-05-01 | 深圳领济生物科技有限公司 | New recruitment element for ubiquitin ligase and use thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1185244C (en) * | 1999-01-18 | 2005-01-19 | 郑州大学 | Rebescensine A derivatives and preparing process thereof |
| EP1487434B1 (en) * | 2002-03-06 | 2007-05-09 | The Medical Research and Education Trust | Botanical extract compositions with anti-cancer activity comprising isoliquiritigenin |
-
2004
- 2004-03-11 CN CNB2004100168916A patent/CN1329083C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007051390A1 (en) * | 2005-11-07 | 2007-05-10 | Rui Jin Hospital Affiliated To Shanghai Second Medical University | The use of eriocalyxin b in the manufacture of medicaments for treating leukemia |
| WO2008022505A1 (en) * | 2006-08-18 | 2008-02-28 | Rui Jin Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine | Use of rubescensine a and derivatives thereof in pharmacy |
| WO2014048109A1 (en) * | 2012-09-29 | 2014-04-03 | 中山大学 | Reagent for targeting degradation of bcr-abl protein and use in preparation of philadelphia chromosome-positive tumor-curing medicine |
| WO2025087245A1 (en) * | 2023-10-23 | 2025-05-01 | 深圳领济生物科技有限公司 | New recruitment element for ubiquitin ligase and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1329083C (en) | 2007-08-01 |
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