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

• Published in: Clinical cancer research Vol. 25; no. 20; pp. 6260 - 6273
• Main Authors: Lucas, Fabienne, Rogers, Kerry A, Harrington, Bonnie K, Pan, Alexander, Yu, Lianbo, Breitbach, Justin, Bundschuh, Ralf, Goettl, Virginia M, Hing, Zachary A, Kanga, Parviz, Mantel, Rose, Sampath, Deepa, Smith, Lisa L, Wasmuth, Ronni, White, Danielle K, Yan, Pearlly, Byrd, John C, Lapalombella, Rosa, Woyach, Jennifer A
• Format: Journal Article
• Language: English
• Published: United States 15.10.2019
• Subjects: Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor - methods; Exportin 1 Protein; Female; Humans; Karyopherins - antagonists & inhibitors; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - pathology; Male; Mice; Mice, Transgenic; Neoplasms, Multiple Primary - genetics; Neoplasms, Multiple Primary - pathology; Proof of Concept Study; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-myc - genetics; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Tumor Cells, Cultured - transplantation
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-0273

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. 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. 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. The Eμ-TCL1xMyc mouse is a new preclinical tool for testing experimental drugs for aggressive B-cell lymphoma, including in the context of CLL.