CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis.
CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis.
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CREBBP/EP300 突变通过 FBXW7-NOTCH-CCL2/CSF1 轴改变肿瘤相关巨噬细胞极化，促进弥漫性大 B 细胞淋巴瘤的肿瘤进展。
DOI：
10.1038/s41392-020-00437-8
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发表时间：
2021-01-11
影响因子：
39.3
通讯作者：
Zhao WL
中科院分区：
文献类型：
--
作者：
Huang YH;Cai K;Xu PP;Wang L;Huang CX;Fang Y;Cheng S;Sun XJ;Liu F;Huang JY;Ji MM;Zhao WL
表观遗传学改变在弥漫性大B细胞淋巴瘤（DLBCL）的肿瘤进展中起重要作用。然而，表观遗传基因突变对肿瘤微环境的生物学相关性仍有待确定。通过全基因组/外显子组测序（WGS/WES）在316例患者的训练队列中和通过靶向测序在303例新诊断DLBCL患者的验证队列中检测与组蛋白甲基化（KMT2D、KMT2C、EZH2）、组蛋白乙酰化（CREBBP、EP300）、DNA甲基化（TET2）和染色质重塑（ARID1A）相关的核心基因集。评估了它们与外周血免疫细胞和临床结果的相关性。在体外和体内研究了肿瘤微环境的潜在机制。在所有619例DLBCL患者中，KMT2D（19.5%）的体细胞突变最常见，其次是ARID1A（8.7%），CREBBP（8.4%），KMT2C（8.2%），TET2（7.8%），EP300（6.8%）和EZH2（2.9%）的突变。其中，CREBBP/EP300突变与外周血淋巴细胞/单核细胞绝对比值降低以及无进展生存期和总生存期较差显著相关。在B淋巴瘤细胞中，CREBBP或EP 300的突变或敲低抑制H3K27乙酰化，下调FBXW7表达，激活NOTCH通路和下游CCL 2/CSF 1表达，导致肿瘤相关巨噬细胞极化为M2表型和肿瘤细胞增殖。在B淋巴瘤小鼠模型中，携带CREBBP/EP 300突变的异种移植肿瘤表现出较低的H3K27乙酰化，较高的M2巨噬细胞募集，以及通过FBXW7-NOTCH-CCL2/CSF 1轴比携带CREBBP/EP 300野生型对照的肿瘤更快的肿瘤生长。因此，我们的工作有助于理解异常组蛋白乙酰化调节肿瘤微环境作为一种替代机制的DLBCL肿瘤进展。
Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma (DLBCL). However, the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined. The core set of genes relating to histone methylation (KMT2D, KMT2C, EZH2), histone acetylation (CREBBP, EP300), DNA methylation (TET2), and chromatin remodeling (ARID1A) were detected in the training cohort of 316 patients by whole-genome/exome sequencing (WGS/WES) and in the validation cohort of 303 patients with newly diagnosed DLBCL by targeted sequencing. Their correlation with peripheral blood immune cells and clinical outcomes were assessed. Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo. Among all 619 DLBCL patients, somatic mutations in KMT2D (19.5%) were most frequently observed, followed by mutations in ARID1A (8.7%), CREBBP (8.4%), KMT2C (8.2%), TET2 (7.8%), EP300 (6.8%), and EZH2 (2.9%). Among them, CREBBP/EP300 mutations were significantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios, as well as inferior progression-free and overall survival. In B-lymphoma cells, the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation, downregulated FBXW7 expression, activated the NOTCH pathway, and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation. In B-lymphoma murine models, xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation, higher M2 macrophage recruitment, and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis. Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL.
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影响因子：
37.3
作者：
Camicia R;Winkler HC;Hassa PO
通讯作者：
Hassa PO
肿瘤相关巨噬细胞预测弥漫性大 B 细胞淋巴瘤的预后及其与外周绝对单核细胞计数的相关性
影响因子：
3.8
作者：
Li, Yan-Li;Shi, Zhi-Hu;Zhai, Zhi-Min
通讯作者：
Zhai, Zhi-Min
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影响因子：
10.1
作者：
Ji MM;Huang YH;Huang JY;Wang ZF;Fu D;Liu H;Liu F;Leboeuf C;Wang L;Ye J;Lu YM;Janin A;Cheng S;Zhao WL
通讯作者：
Zhao WL
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影响因子：
5.8
作者：
Che, Fengyuan;Heng, Xueyuan;Wang, Lijuan
通讯作者：
Wang, Lijuan
影响因子：
82.9
作者：
Chapuy B;Stewart C;Dunford AJ;Kim J;Kamburov A;Redd RA;Lawrence MS;Roemer MGM;Li AJ;Ziepert M;Staiger AM;Wala JA;Ducar MD;Leshchiner I;Rheinbay E;Taylor-Weiner A;Coughlin CA;Hess JM;Pedamallu CS;Livitz D;Rosebrock D;Rosenberg M;Tracy AA;Horn H;van Hummelen P;Feldman AL;Link BK;Novak AJ;Cerhan JR;Habermann TM;Siebert R;Rosenwald A;Thorner AR;Meyerson ML;Golub TR;Beroukhim R;Wulf GG;Ott G;Rodig SJ;Monti S;Neuberg DS;Loeffler M;Pfreundschuh M;Trümper L;Getz G;Shipp MA
通讯作者：
Shipp MA