Cell of Origin and Immunologic Events in the Pathogenesis of Breast Implant–Associated Anaplastic Large-Cell Lymphoma

Turner, Suzanne; Inghirami, Giorgio; Miranda, Roberto N.; Kadin, Marshall E.

doi:10.1016/j.ajpath.2019.09.005

Cited by 42 publications

(32 citation statements)

References 80 publications

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“…The data confirmed the presence of a dominant clone, which became increasingly exclusive within the 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.…”

Section: Clinical Data and Bia-alcl Pdtx Model Establishmentsupporting

confidence: 82%

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

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et al. 2020

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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.

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Section: Clinical Data and Bia-alcl Pdtx Model Establishmentsupporting

confidence: 82%

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

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et al. 2020

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“…They belong to the TH17 gene signature [90], supporting the indicated character of ALCL. Breast implant-associated (BIA)-ALCL, CTLC and ALCL are closely related malignancies and consistently express several aspects of ILC3/TH17 cells aberrantly [28,69,91]. In CTCL, IL17F expression is driven via the IL2-JAK3-STAT5 pathway reportedly activated by a particular mutation of SOCS1 [69].…”

Section: Discussionmentioning

confidence: 99%

The NKL-code for innate lymphoid cells reveals deregulated expression of NKL homeobox genes HHEX and HLX in anaplastic large cell lymphoma (ALCL)

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NKL homeobox genes encode developmental transcription factors and display an NKL-code according to their physiological expression pattern in hematopoiesis. Here, we analyzed public transcriptome data from primary innate lymphoid cells (ILCs) for NKL homeobox gene activities and found that ILC3 expressed exclusively HHEX while in ILC1 and ILC2 these genes were silenced. Deregulation of the NKL-code promotes hematopoietic malignancies, including anaplastic large cell lymphoma (ALCL) which reportedly may derive from ILC3. Accordingly, we analyzed NKL homeobox gene activities in ALCL cell lines and investigated their role in this malignancy. Transcriptome analyses demonstrated low expression levels of HHEX but powerfully activated HLX. Forced expression of HHEX in ALCL cell lines induced genes involved in apoptosis and ILC3 differentiation, indicating tumor suppressor activity. ALCL associated NPM1-ALK and JAK-STAT3-signalling drove enhanced expression of HLX while discounting HHEX. Genomic profiling revealed copy number gains at the loci of HLX and STAT3 in addition to genes encoding both STAT3 regulators (AURKA,

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“…Hypotheses proposed regarding the pathogenesis of BIA-ALCL include chronic inflammation driven by a bacterial biofilm, microparticles shed from the implant shell, repetitive trauma/friction between the implant shell and the capsule, carcinogenic toxins leaching from the implant or genetic predisposition. 39,40,53,[58][59][60][61][62][63][64] Details of ongoing active UK research studies can be found here: https://www.cancerresearchuk.org/ about-cancer/find-a-clinical-trial/a-study-find-more-about-ca uses-breast-implant-associated-anaplastic-large-cell-lym phoma-bia-alcl, and clinicians are encouraged to contact the investigators for further details. It is hoped that in the future, a centralised biobank of samples for research purposes can be developed.…”

Section: Secondary Assessmentmentioning

confidence: 99%

UK Guidelines on the Diagnosis and Treatment of Breast Implant‐Associated Anaplastic Large Cell Lymphoma on behalf of the Medicines and Healthcare products Regulatory Agency Plastic, Reconstructive and Aesthetic Surgery Expert Advisory Group

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Summary Breast implant‐associated anaplastic large cell lymphoma (BIA‐ALCL) is an uncommon T‐cell non‐Hodgkin Lymphoma (NHL) associated with breast implants. Raising awareness of the possibility of BIA‐ALCL in anyone with breast implants and new breast symptoms is crucial to early diagnosis. The tumour begins on the inner aspect of the peri‐implant capsule causing an effusion, or less commonly a tissue mass to form within the capsule, which may spread locally or to more distant sites in the body. Diagnosis is usually made by cytological, immunohistochemical and immunophenotypic evaluation of the aspirated peri‐implant fluid: pleomorphic lymphocytes are characteristically anaplastic lymphoma kinase (ALK)‐negative and strongly positive for CD30. BIA‐ALCL is indolent in most patients but can progress rapidly. Surgical removal of the implant with the intact surrounding capsule (total en‐bloc capsulectomy) is usually curative. Late diagnosis may require more radical surgery and systemic therapies and although these are usually successful, poor outcomes and deaths have been reported. By adopting a structured approach, as suggested in these guidelines, early diagnosis and successful treatment will minimise the need for systemic treatments, reduce morbidity and the risk of poor outcomes.

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Cell of Origin and Immunologic Events in the Pathogenesis of Breast Implant–Associated Anaplastic Large-Cell Lymphoma

Abstract: Disclosures: M.E.K., G.I., and R.N.M. have served on scientific advisory boards on breast implanteassociated anaplastic large-cell lymphoma (BIA-ALCL) for Allergan; S.D.T. has served on scientific advisory boards on BIA-ALCL for Allergan without remuneration.

Cited by 42 publications

References 80 publications

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

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

The NKL-code for innate lymphoid cells reveals deregulated expression of NKL homeobox genes HHEX and HLX in anaplastic large cell lymphoma (ALCL)

UK Guidelines on the Diagnosis and Treatment of Breast Implant‐Associated Anaplastic Large Cell Lymphoma on behalf of the Medicines and Healthcare products Regulatory Agency Plastic, Reconstructive and Aesthetic Surgery Expert Advisory Group

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