Eμ-TCL1xMyc: A Novel Mouse Model for Concurrent CLL and B-Cell Lymphoma.

Autor:	Lucas F; Division of Hematology, The Ohio State University, Columbus, Ohio., Rogers KA; Division of Hematology, The Ohio State University, Columbus, Ohio., Harrington BK; Division of Hematology, The Ohio State University, Columbus, Ohio.; Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio., Pan A; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio., Yu L; Center for Biostatistics, Department of Bioinformatics, The Ohio State University, Columbus, Ohio., Breitbach J; Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio., Bundschuh R; Division of Hematology, The Ohio State University, Columbus, Ohio.; Department of Physics, Department of Chemistry & Biochemistry, The Ohio State University, Columbus, Ohio., Goettl VM; Division of Hematology, The Ohio State University, Columbus, Ohio., Hing ZA; Division of Hematology, The Ohio State University, Columbus, Ohio.; Medical Scientist Training Program, The Ohio State University, Columbus, Ohio., Kanga P; Division of Hematology, The Ohio State University, Columbus, Ohio., Mantel R; Division of Hematology, The Ohio State University, Columbus, Ohio., Sampath D; Division of Hematology, The Ohio State University, Columbus, Ohio., Smith LL; Division of Hematology, The Ohio State University, Columbus, Ohio., Wasmuth R; Division of Hematology, The Ohio State University, Columbus, Ohio., White DK; Division of Hematology, The Ohio State University, Columbus, Ohio., Yan P; Division of Hematology, The Ohio State University, Columbus, Ohio., Byrd JC; Division of Hematology, The Ohio State University, Columbus, Ohio., Lapalombella R; Division of Hematology, The Ohio State University, Columbus, Ohio., Woyach JA; Division of Hematology, The Ohio State University, Columbus, Ohio. jennifer.woyach@osumc.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Oct 15; Vol. 25 (20), pp. 6260-6273. Date of Electronic Publication: 2019 Jul 11.
DOI:	10.1158/1078-0432.CCR-19-0273
Abstrakt:	Purpose: Aberrant Myc expression is a major factor in the pathogenesis of aggressive lymphoma, and these lymphomas, while clinically heterogeneous, often are resistant to currently available treatments and have poor survival. Myc expression can also be seen in aggressive lymphomas that are observed in the context of CLL, and we sought to develop a mouse model that could be used to study therapeutic strategies for aggressive lymphoma in the context of CLL. Experimental Design: We crossed the Eμ-TCL1 mouse model with the Eμ-Myc mouse model to investigate the clinical phenotype associated with B-cell-restricted expression of these oncogenes. The resulting malignancy was then extensively characterized, from both a clinical and biologic perspective. Results: Eμ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically, immunophenotypically, and molecularly distinct concurrent CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WT mice established a disease similar to that in the double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was, however, observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma. Conclusions: The Eμ-TCL1xMyc mouse is a new preclinical tool for testing experimental drugs for aggressive B-cell lymphoma, including in the context of CLL. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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