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A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries

1
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
2
Department of Translational and Precision Medicine, Sapienza University of Rome, 00161 Rome, Italy
3
Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY 10065, USA
4
Department of Medicine, Hematology-Oncology, Weill Cornell Medicine and the New York Presbyterian Hospital, New York, NY 10065, USA
5
Department of Systems Biology and Biomedical Informatics, Columbia University, New York, NY 10032, USA
6
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
7
Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy
8
Departments of Pathology and Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
9
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
10
Department of Medicine and Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA
11
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(6), 1603; https://doi.org/10.3390/cancers12061603
Received: 19 May 2020 / Revised: 8 June 2020 / Accepted: 11 June 2020 / Published: 17 June 2020
Breast implant-associated lymphoma (BIA-ALCL) has recently been recognized as an independent peripheral T-cell lymphoma (PTCL) entity. In this study, we generated the first BIA-ALCL patient-derived tumor xenograft (PDTX) model (IL89) and a matching continuous cell line (IL89_CL#3488) to discover potential vulnerabilities and druggable targets. We characterized IL89 and IL89_CL#3488, both phenotypically and genotypically, and demonstrated that they closely resemble the matching human primary lymphoma. The tumor content underwent significant enrichment along passages, as confirmed by the increased variant allele frequency (VAF) of mutations. Known aberrations (JAK1 and KMT2C) were identified, together with novel hits, including PDGFB, PDGFRA, and SETBP1. A deep sequencing approach allowed the detection of mutations below the Whole Exome Sequencing (WES) sensitivity threshold, including JAK1G1097D, in the primary sample. RNA sequencing confirmed the expression of a signature of differentially expressed genes in BIA-ALCL. Next, we tested IL89’s sensitivity to the JAK inhibitor ruxolitinib and observed a potent anti-tumor effect, both in vitro and in vivo. We also implemented a high-throughput drug screening approach to identify compounds associated with increased responses in the presence of ruxolitinib. In conclusion, these new IL89 BIA-ALCL models closely recapitulate the primary correspondent lymphoma and represent an informative platform for dissecting the molecular features of BIA-ALCL and performing pre-clinical drug discovery studies, fostering the development of new precision medicine approaches. View Full-Text
Keywords: patient-derived tumor xenograft; JAK/STAT pathway; pre-clinical model; drug discovery; precision medicine patient-derived tumor xenograft; JAK/STAT pathway; pre-clinical model; drug discovery; precision medicine
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MDPI and ACS Style

Fiore, D.; Cappelli, L.V.; Zumbo, P.; Phillips, J.M.; Liu, Z.; Cheng, S.; Yoffe, L.; Ghione, P.; Di Maggio, F.; Dogan, A.; Khodos, I.; de Stanchina, E.; Casano, J.; Kayembe, C.; Tam, W.; Betel, D.; Foa’, R.; Cerchietti, L.; Rabadan, R.; Horwitz, S.; Weinstock, D.M.; Inghirami, G. A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries. Cancers 2020, 12, 1603. https://doi.org/10.3390/cancers12061603

AMA Style

Fiore D, Cappelli LV, Zumbo P, Phillips JM, Liu Z, Cheng S, Yoffe L, Ghione P, Di Maggio F, Dogan A, Khodos I, de Stanchina E, Casano J, Kayembe C, Tam W, Betel D, Foa’ R, Cerchietti L, Rabadan R, Horwitz S, Weinstock DM, Inghirami G. A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries. Cancers. 2020; 12(6):1603. https://doi.org/10.3390/cancers12061603

Chicago/Turabian Style

Fiore, Danilo, Luca V. Cappelli, Paul Zumbo, Jude M. Phillips, Zhaoqi Liu, Shuhua Cheng, Liron Yoffe, Paola Ghione, Federica Di Maggio, Ahmet Dogan, Inna Khodos, Elisa de Stanchina, Joseph Casano, Clarisse Kayembe, Wayne Tam, Doron Betel, Robin Foa’, Leandro Cerchietti, Raul Rabadan, Steven Horwitz, David M. Weinstock, and Giorgio Inghirami. 2020. "A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries" Cancers 12, no. 6: 1603. https://doi.org/10.3390/cancers12061603

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