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

Danilo Fiore,Leandro Cerchietti,Liron Yoffe,Paul Zumbo,Doron Betel,Clarisse Kayembe,Inna Khodos,David M Weinstock,Giorgio Inghirami,Paola Ghione,Joseph Casano,Shuhua Cheng,Zhaoqi Liu,Luca Vincenzo Cappelli,Wayne Tam,Elisa De Stanchina,Ahmet Doğan ,Robin Foà ,Raúl Rabadán ,Jude M Phillip ,Steven M Horwitz ,Federica Maggio

doi:10.3390/cancers12061603

Abstract

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.

Highlights

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare disease that has recently been categorized by the World Health Organization (WHO) as an independent subtype of peripheral T-cell lymphoma (PTCL) [1]
The data confirmed the presence of a dominant clone, which became increasingly exclusive within the patient-derived tumor xenograft (PDTX) samples (Figure 1E), and the data were further confirmed with multiple primers (Figure S1C). These findings demonstrated that the IL89 primary sample included a relatively large number of normal T-cells, as previously described [32], which were lost along with PDTX engraftment
We found hits in genes described to be mutated in BIA-ALCL [9] (i.e., JAK1, KMT2C, and EOMES) and the variant allele frequency (VAF) of almost all the driver mutations increased from the primary sample to the PDTX

Summary

Introduction

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare disease that has recently been categorized by the World Health Organization (WHO) as an independent subtype of peripheral T-cell lymphoma (PTCL) [1]. As of July 2019, a total of 573 cases have been identified within the United States [2,3], with 33 deaths reported. The majority of patients manifest either seroma and/or in situ disease, both of which are associated with an excellent prognosis (89% overall survival rate at 5 years from the diagnosis) [6]. The excellent prognosis, and incomplete reporting, there is an increasing interest in investigating BIA-ALCL incidence, risk factors, and outcome, mainly dictated by the evidence that breast augmentation is the number-one cosmetic procedure performed in the United States [8]. Scientific progress has been somewhat hampered by the lack of informative pre-clinical models

Methods

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Discussion

Conclusion