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炎症通过上调 AID 加速了 BCR-ABL1+ B-ALL 的发展。

Inflammation accelerates BCR-ABL1+ B-ALL development through upregulation of AID.

机构信息

Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.

Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, China.

出版信息

Blood Adv. 2022 Jul 12;6(13):4060-4072. doi: 10.1182/bloodadvances.2021005017.

DOI:10.1182/bloodadvances.2021005017
PMID:35816360
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9278295/
Abstract

Inflammation contributes to the initiation and disease progression of several lymphoid malignancies. BCR-ABL1-positive B-cell acute lymphoblastic leukemia (BCR-ABL1+ B-ALL) is triggered by the malignant cloning of immature B cells promoted by the BCR-ABL1 fusion gene. However, it is unclear whether the mechanism driving the disease progression of BCR-ABL1+ B-ALL involves inflammatory stimulation. Here, we evaluate BCR-ABL1+ B-ALL cells' response to inflammatory stimuli lipopolysaccharide (LPS) in vitro and in vivo. The results indicate that LPS promotes cell growth and genomic instability in cultured BCR-ABL1+ B-ALL cells and accelerates the BCR-ABL1+ B-ALL development in a mouse model. We show that the LPS-induced upregulation of activation-induced deaminase (AID) is required for the cell growth and disease progression of BCR-ABL1+ B-ALL. Moreover, AID modulates the expression of various genes that are dominated by suppressing apoptosis genes and upregulating DNA damage-repair genes. These genes lead to facilitation for BCR-ABL1+ B-ALL progression. The heat shock protein 90 (Hsp90) inhibitors significantly reduce AID protein level and delay the disease progression of BCR-ABL1+ B-ALL upon inflammatory stimulation. The present data demonstrate the causative role of AID in the development and progression of BCR-ABL1+ B-ALL during inflammation, thus highlighting potential therapeutic targets.

摘要

炎症有助于几种淋巴恶性肿瘤的起始和疾病进展。BCR-ABL1 阳性 B 细胞急性淋巴细胞白血病 (BCR-ABL1+B-ALL) 是由 BCR-ABL1 融合基因促进的不成熟 B 细胞恶性克隆引发的。然而，尚不清楚驱动 BCR-ABL1+B-ALL 疾病进展的机制是否涉及炎症刺激。在这里，我们评估了 BCR-ABL1+B-ALL 细胞对体外和体内炎症刺激物脂多糖 (LPS) 的反应。结果表明，LPS 促进培养的 BCR-ABL1+B-ALL 细胞的细胞生长和基因组不稳定性，并加速小鼠模型中 BCR-ABL1+B-ALL 的发展。我们表明，LPS 诱导的激活诱导脱氨酶 (AID) 的上调是 BCR-ABL1+B-ALL 细胞生长和疾病进展所必需的。此外，AID 调节各种基因的表达，这些基因主要通过抑制凋亡基因和上调 DNA 损伤修复基因来促进 BCR-ABL1+B-ALL 的进展。这些基因导致 BCR-ABL1+B-ALL 的进展。热休克蛋白 90 (Hsp90) 抑制剂可显著降低 AID 蛋白水平，并在炎症刺激时延迟 BCR-ABL1+B-ALL 的疾病进展。这些数据表明 AID 在炎症期间 BCR-ABL1+B-ALL 的发展和进展中起因果作用，从而突出了潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a98a/9278295/43ff0fa772cb/advancesADV2021005017f6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a98a/9278295/2616ebed9b95/advancesADV2021005017f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a98a/9278295/43ff0fa772cb/advancesADV2021005017f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a98a/9278295/01a62ec8b60d/advancesADV2021005017absf1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a98a/9278295/5ab9b26f5989/advancesADV2021005017f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a98a/9278295/919885a78bef/advancesADV2021005017f2.jpg
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