TY - JOUR
T1 - Eμ-TCL1xMyc
T2 - A novel mouse model for concurrent CLL and B-Cell lymphoma
AU - Lucas, Fabienne
AU - Rogers, Kerry A.
AU - Harrington, Bonnie K.
AU - Pan, Alexander
AU - Yu, Lianbo
AU - Breitbach, Justin
AU - Bundschuh, Ralf
AU - Goettl, Virginia M.
AU - Hing, Zachary A.
AU - Kanga, Parviz
AU - Mantel, Rose
AU - Sampath, Deepa
AU - Smith, Lisa L.
AU - Wasmuth, Ronni
AU - White, Danielle K.
AU - Yan, Pearlly
AU - Byrd, John C.
AU - Lapalombella, Rosa
AU - Woyach, Jennifer A.
N1 - Funding Information:
Dr. Dalia El-Gamal provided initial technical assistance. Alan Flechtner, Florinda Jaynes, and The Ohio State University Comparative Pathology & Mouse Phenotyping Shared Resource (funded by a Cancer Center Support Grant P30 CA016058) supported pathology studies. Flow sorting was supported by Jennifer Mele. Transcriptomic library generation and sequencing were supported by Xi Chen and The Ohio State University Genomics Shared Resource (supported in part by Cancer Center Support grant P30 CA016058). Computational resources were provided by Ohio Supercomputer Center. The authors thank Karyopharm Therapeutics for providing KPT-8602. This work was supported by NCI grants R35 CA197734 (to J.C. Byrd), R01 CA214046 (to R. Lapalombella and J.C. Byrd), K23 CA178183 (to J.A. Woyach), R01 CA177292 (to J.C. Byrd and J.A. Woyach), and R01 CA192928 (to R. Lapalombella, J.C. Byrd, and J.A. Woyach); the Leukemia andLymphomaSociety;aResearchScholargrant(129863-RSG-16-158-01-CDD) from the American Cancer Society; and The OSU Comprehensive Cancer Center NCIP30 CA 016058 and Pelotonia funds.
Funding Information:
Dr. Dalia El-Gamal provided initial technical assistance. Alan Flechtner, Florinda Jaynes, and The Ohio State University Comparative Pathology & Mouse Phenotyping Shared Resource (funded by a Cancer Center Support Grant P30 CA016058) supported pathology studies. Flow sorting was supported by Jennifer Mele. Transcriptomic library generation and sequencingwere supported by Xi Chen and The Ohio State University Genomics Shared Resource (supported in part by Cancer Center Support grant P30 CA016058). Computational resources were provided by Ohio Supercomputer Center. The authors thank Karyopharm Therapeutics for providing KPT-8602. This work was supported by NCI grants R35 CA197734 (to J.C. Byrd), R01 CA214046 (to R. Lapalombella and J.C. Byrd), K23 CA178183 (to J.A. Woyach), R01 CA177292 (to J.C. Byrd and J.A. Woyach), and R01 CA192928 (to R. Lapalombella, J.C. Byrd, and J.A. Woyach); the Leukemia and LymphomaSociety; a Research Scholar grant (129863-RSG-16-158-01-CDD) from the American Cancer Society; and The OSU Comprehensive Cancer Center NCIP30 CA 016058 and Pelotonia funds.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/10/15
Y1 - 2019/10/15
N2 - 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 acompound 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.
AB - 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 acompound 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.
UR - http://www.scopus.com/inward/record.url?scp=85073312020&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073312020&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-0273
DO - 10.1158/1078-0432.CCR-19-0273
M3 - Article
C2 - 31296529
AN - SCOPUS:85073312020
SN - 1078-0432
VL - 25
SP - 6260
EP - 6273
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -