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Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1714-1724
Non-Hodgkin Lymphoma
Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma
Naoki Oishi,1,2 Tanya Hundal,1 Jessica L. Phillips,1 Surendra Dasari,1
Guangzhen Hu,1 David S. Viswanatha,1 Rong He,1 Ming Mai,1 Hailey K. Jacobs,1
Nada H. Ahmed,1,3 Sergei I. Syrbu,4 Youssef Salama,1 Jennifer R. Chapman,5
Francisco Vega,5° Jagmohan Sidhu,6 N. Nora Bennani,7 Alan L. Epstein,8 L.
Jeffrey Medeiros,9 Mark W. Clemens,10# Roberto N. Miranda9# and Andrew L.
1# Feldman
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; 2Department of Pathology, University of Yamanashi, Chuo, Yamanashi, Japan; 3Department of Clinical Pathology, Suez Canal University, Ismailia, Egypt; 4Department of Pathology, University of Iowa, Iowa City, IA, USA; 5Department of Pathology, University of Miami, Miami, FL, USA; 6Department of Pathology and Laboratory Medicine, United Health Services, Binghamton, NY, USA; 7Division of Hematology, Mayo Clinic, Rochester, MN, USA; 8Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; 9Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA and 10Department of Plastic Surgery, MD Anderson Cancer Center, Houston, TX, USA
°Current affiliation: Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA #MWC, RNM, and ALF contributed equally as co-senior authors.
ABSTRACT
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 recon- structive 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-BIA- ALCL 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 pro- portional to upregulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA- ALCL 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 therapeu- tic targets in this disease.
Correspondence:
ANDREW L. FELDMAN
feldman.andrew@mayo.edu
Received: December 20, 2019. Accepted: May 14, 2020. Pre-published: May 15, 2020.
https://doi.org/10.3324/haematol.2019.245860
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