論文

査読有り 国際誌
2020年5月15日

Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma.

Haematologica
  • Naoki Oishi
  • Tanya Hundal
  • Jessica L Phillips
  • Surendra Dasari
  • Guangzhen Hu
  • David S Viswanatha
  • Rong He
  • Ming Mai
  • Hailey K Jacobs
  • Nada H Ahmed
  • Sergei I Syrbu
  • Youssef Salama
  • Jennifer R Chapman
  • Francisco Vega
  • Jagmohan Sidhu
  • N Nora Bennani
  • Alan L Epstein
  • L Jeffrey Medeiros
  • Mark W Clemens
  • Roberto N Miranda
  • Andrew L Feldman
  • 全て表示

106
6
開始ページ
1714
終了ページ
1724
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.3324/haematol.2019.245860

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) 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 ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. 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 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.

リンク情報
DOI
https://doi.org/10.3324/haematol.2019.245860
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32414854
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168507
ID情報
  • DOI : 10.3324/haematol.2019.245860
  • PubMed ID : 32414854
  • PubMed Central 記事ID : PMC8168507

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