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泛素和 SUMO 缀合作为急性髓系白血病对化疗反应的生物标志物。

Ubiquitin and SUMO conjugation as biomarkers of acute myeloid leukemias response to chemotherapies.

机构信息

Institut de Génétique Moléculaire de Montpellier (IGMM), University of Montpellier, CNRS, Montpellier, France.

Equipe Labellisée Ligue Contre le Cancer, Paris, France.

出版信息

Life Sci Alliance. 2020 Apr 17;3(6). doi: 10.26508/lsa.201900577. Print 2020 Jun.

DOI:10.26508/lsa.201900577
PMID:32303586
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7167290/
Abstract

Ubiquitin and the ubiquitin-like SUMO are covalently conjugated to thousands of proteins to modulate their function and fate. Many of the enzymes involved in their conjugation are dysregulated in cancers and involved in cancer cell response to therapies. We describe here the identification of biomarkers of the activity of these enzymes and their use to predict acute myeloid leukemias (AML) response to standard chemotherapy (daunorubicin-DNR and cytarabine-Ara-C). We compared the ability of extracts from chemosensitive and chemoresistant AML cells to conjugate ubiquitin or SUMO-1 on 9,000 proteins spotted on protein arrays. We identified 122 proteins whose conjugation by these posttranslational modifiers marks AML resistance to DNR and/or Ara-C. Based on this signature, we defined a statistical score predicting AML patient response to standard chemotherapy. We finally developed a miniaturized assay allowing for easy assessment of modification levels of the selected biomarkers and validated it in patient cell extracts. Thus, our work identifies a new type of ubiquitin-based biomarkers that could be used to predict cancer patient response to treatments.

摘要

泛素和类泛素 SUMO 被共价连接到数千种蛋白质上，以调节它们的功能和命运。许多参与其连接的酶在癌症中失调，并参与癌细胞对治疗的反应。我们在这里描述了这些酶活性的生物标志物的鉴定及其在预测急性髓细胞白血病 (AML) 对标准化疗 (柔红霉素-DNR 和阿糖胞苷-Ara-C) 反应中的用途。我们比较了化疗敏感和耐药 AML 细胞提取物在蛋白质阵列上点样的 9000 种蛋白质上连接泛素或 SUMO-1 的能力。我们鉴定了 122 种蛋白质，这些翻译后修饰物的连接标志着 AML 对 DNR 和/或 Ara-C 的耐药性。基于这个特征，我们定义了一个统计评分来预测 AML 患者对标准化疗的反应。最后，我们开发了一种微型化测定法，可轻松评估所选生物标志物的修饰水平，并在患者细胞提取物中进行了验证。因此，我们的工作确定了一种新的基于泛素的生物标志物，可用于预测癌症患者对治疗的反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/ed0e6ea656dd/LSA-2019-00577_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/e368729ff63f/LSA-2019-00577_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/4c6e8849dfe7/LSA-2019-00577_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/33d646a41ae8/LSA-2019-00577_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/8c8e169119ec/LSA-2019-00577_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/d94445df8bcb/LSA-2019-00577_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/75b3024281da/LSA-2019-00577_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/ed0e6ea656dd/LSA-2019-00577_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/e368729ff63f/LSA-2019-00577_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/4c6e8849dfe7/LSA-2019-00577_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/33d646a41ae8/LSA-2019-00577_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/8c8e169119ec/LSA-2019-00577_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/d94445df8bcb/LSA-2019-00577_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/75b3024281da/LSA-2019-00577_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/102c/7167290/ed0e6ea656dd/LSA-2019-00577_Fig4.jpg

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