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时间多组学建模揭示慢性淋巴细胞白血病中 B 细胞受体增殖程序。

Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia.

机构信息

Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France.

出版信息

Leukemia. 2021 May;35(5):1463-1474. doi: 10.1038/s41375-021-01221-5. Epub 2021 Apr 8.

DOI:10.1038/s41375-021-01221-5
PMID:33833385
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8102193/
Abstract

B-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand-receptor interactions.

摘要

B 细胞受体 (BCR) 信号对于大多数成熟 B 细胞淋巴瘤/白血病的病理生理学至关重要，并且已经成为治疗靶点，但其有效性仍然受到突变的发生的限制。因此，破译该途径下游的细胞程序已成为开发创新疗法的重中之重。我们使用 BCR 诱导的慢性淋巴细胞白血病细胞增殖的原始体外模型，在 BCR 激活后 1 小时到 4 天内生成了 108 个时间转录组和蛋白质组图谱。该数据集揭示了一个由 13065 个转录本和 4027 个蛋白质组成的结构化时间反应，包括由 430 个基因和 374 个蛋白质组成的白血病增殖特征。对这种复杂细胞反应的数学建模进一步突出了由 14 个早期基因驱动的转录网络，这些基因与参与细胞增殖的蛋白质有关。这组基因包括预期的基因（EGR1/2、NF-kB）和参与 NF-kB 信号调节（TANK、ROHF）和免疫逃避（KMO、IL4I1）的基因，这些基因尚未与白血病细胞增殖相关联。我们的研究揭示了原发性白血病细胞中 BCR 激活的增殖遗传程序。这种结合时间测量和建模的方法可以识别新型潜在靶点，用于治疗淋巴恶性肿瘤和依赖配体-受体相互作用的癌症。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/642bd5b33820/41375_2021_1221_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/85f0d66efc72/41375_2021_1221_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/4483450ac5bf/41375_2021_1221_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/cb2fd84930c1/41375_2021_1221_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/a0e72867968c/41375_2021_1221_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/849e5dc74f4a/41375_2021_1221_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/642bd5b33820/41375_2021_1221_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/85f0d66efc72/41375_2021_1221_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/4483450ac5bf/41375_2021_1221_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/cb2fd84930c1/41375_2021_1221_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/a0e72867968c/41375_2021_1221_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/849e5dc74f4a/41375_2021_1221_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c9b/8102193/642bd5b33820/41375_2021_1221_Fig6_HTML.jpg

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