Editors' ChoiceCancer

Recycling resected tonsils for lymphoma research

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Science Translational Medicine  13 Nov 2019:
Vol. 11, Issue 518, eaaz9751
DOI: 10.1126/scitranslmed.aaz9751

Abstract

Tonsillectomy samples can be used to generate in vitro models of high-grade B cell lymphoma.

In vitro models for cancer are invaluable tools for biological research and testing of potential therapies. Lymphomas are tumors of the immune system, for which improved in vitro models are required. Caeser et al. now describe an in vitro model system for B cell lymphomas, by harnessing the availability of nonmalignant lymphoid tissue from tonsillectomies, a commonly performed surgery.

Tonsils are lymphoid organs in the oral cavity that are enriched in germinal centers (GC), the site of B cell maturation. B cells from GCs normally undergo apoptosis without supportive factors, such as CD40 ligand, follicular dendritic cells, and interleukin-21 (IL-21). The authors designed a follicular dendritic-like feeder cell line expressing CD40 ligand and IL-21, which was capable of sustaining the growth of primary B cells from tonsils for up to 10 days. Importantly, they identified SLC20A1 as a highly expressed receptor on primary GC B cells for the GaLV envelope protein, allowing the design of a GaLV fusion lentiviral construct to transduce these cells. Using these constructs, the authors introduced common lymphoma oncogenes into primary GC B cells and found that BCL2 when co-expressed with MYC or BCL6 was able to maintain the cells in long term culture, leading to the establishment of an in vitro model reminiscent of GC subtype diffuse large B cell lymphoma (DLBCL).

The authors demonstrated two interesting applications of their in vitro model. First, they performed a CRISPR screen to interrogate the functional role of commonly mutated genes in DLBCL, identifying a strong tumor-suppressive effect for the G protein subunit GNA13 in addition to established genes, such as p53, CDKN2A, and PTEN. Second, they used the in vitro model to generate “synthetic” cell lines and xenografts with specific combinations of DLBCL oncogenes, resulting in tumors that showed morphological and molecular characteristics of DLBCL.

The generation of an in vitro model with the unique combination of mutations seen in a given patient could theoretically enable the testing of personalized therapeutics in the future. Presently, there remain limitations regarding the logistics for the collection of tonsillectomy samples and the timeline involved in the creation of these models. However, the ability to test defined molecular alterations on genetically normal B cells makes this paper a major technical advance for lymphoma research. It also highlights the value of resected human nonmalignant tissue for cancer research, which could be extended to nonlymphoid cancers.

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