Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma.
Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma.
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DOI：
10.3324/haematol.2019.245860
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发表时间：
2021-06-01
期刊：
影响因子：
10.1
通讯作者：
Feldman AL
中科院分区：
文献类型：
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作者：
Oishi N;Hundal T;Phillips JL;Dasari S;Hu G;Viswanatha DS;He R;Mai M;Jacobs HK;Ahmed NH;Syrbu SI;Salama Y;Chapman JR;Vega F;Sidhu J;Bennani NN;Epstein AL;Medeiros JL;Clemens MW;Miranda RN;Feldman AL
乳房植入物相关间变性大细胞淋巴瘤（BIAALCL）是一种新发现的t细胞恶性肿瘤，它引起了患者对安全性的重大关注，并导致了世界范围内对植入物的使用和接受乳房重建或美容手术患者的临床管理的影响。区分BIA-ALCL与其他间变性大细胞淋巴瘤的分子特征尚未完全阐明，并且BIA-ALCL作为世界卫生组织实体的分类仍然是暂时的。我们对BIA-ALCL与非biaalcl进行了RNA测序和基因集富集分析，发现缺氧信号基因显著上调，包括缺氧相关生物标志物CA9（碳酸酐酶- 9）。免疫组织化学证实了CA9在所有BIA-ALCL中表达，仅在非BIA-ALCL中有少量表达。缺氧条件下培养的bia - alcl衍生细胞系的生长诱导与CA9表达上调成正比，RNA测序显示，与非bia - alcl相比，在BIAALCL组织样本中观察到相同的基因特征。CA9沉默可阻断缺氧诱导的BIA-ALCL细胞生长和细胞周期相关基因表达，而在异种移植小鼠模型中，BIA-ALCL细胞中CA9过表达可促进生长。此外，CA9分泌到BIA-ALCL细胞株上清液中，在人BIA-ALCL血清样本中显著升高。最后，与对照血清相比，移植BIA-ALCL的小鼠血清CA9浓度显著升高。总之，这些发现将BIA-ALCL描述为一种缺氧相关的肿瘤，可能归因于其产生的独特微环境。这些数据支持BIA-ALCL作为一个独特实体的分类，并揭示了研究缺氧相关蛋白（如CA9）作为该疾病的新生物标志物和治疗靶点的机会。
Breast implant-associated anaplastic large cell lymphoma (BIAALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other anaplastic large cell lymphomas have not been fully elucidated and classification of BIA-ALCL as a World Health Organization entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCL to non-BIAALCL and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase- 9). Immunohistochemistry validated CA9 expression in all BIA-ALCL, with only minimal expression in non-BIA-ALCL. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to upregulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIAALCL tissue samples compared to non-BIA-ALCL. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to those in control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.