A novel JAK1 mutant breast implant-associated anaplastic large cell lymphoma patient-derived xenograft fostering pre-clinical discoveries Journal Article

   


Authors: 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.
Article Title: A novel JAK1 mutant breast implant-associated anaplastic large cell lymphoma patient-derived xenograft fostering pre-clinical discoveries
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. © 2020 by the authors.
Keywords: drug discovery; precision medicine; jak/stat pathway; patient-derived tumor xenograft; pre-clinical model
Journal Title: Cancers
Volume: 12
Issue: 6
ISSN: 2072-6694
Publisher: MDPI  
Date Published: 2020-06-01
Start Page: 1603
Language: English
DOI: 10.3390/cancers12061603
PROVIDER: scopus
PUBMED: 32560455
PMCID: PMC7352499
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85086666568&doi=10.3390%2fcancers12061603&partnerID=40&md5=a0c902cac82e7d1bbbc652047d914c8b
Notes: Article -- Export Date: 1 July 2020 -- Source: Scopus
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MSK Authors
  1. Steven M Horwitz
    645 Horwitz
  2. Elisa De Stanchina
    343 De Stanchina
  3. Ahmet Dogan
    454 Dogan
  4. Inna Khodos
    36 Khodos
  5. Paola Ghione
    74 Ghione
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