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Exome sequencing of the TCL1 mouse model for CLL reveals genetic heterogeneity and dynamics during disease development
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Zaborsky, Nadja , Gassner, Franz , Höpner, Jan , Schubert, Maria , Hebenstreit, Daniel, Stark, Richard Jan, Asslaber, Daniela , Steiner, Markus, Geisberger, Roland , Greil, Richard and Egle , Alexander (2019) Exome sequencing of the TCL1 mouse model for CLL reveals genetic heterogeneity and dynamics during disease development. Leukemia, 33 (4). pp. 957-968. doi:10.1038/s41375-018-0260-4 ISSN 0887-6924.
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Official URL: https://doi.org/10.1038/s41375-018-0260-4
Abstract
The TCL1 mouse model is widely used to study pathophysiology, clonal evolution and drug sensitivity or resistance of chronic lymphocytic leukemia (CLL). By performing whole exome sequencing, we present the genetic landscape of primary tumors from TCL1 mice and of TCL1 tumors serially transplanted into wildtype recipients to mimic clonal evolution. We show that similar to CLL patients, mutations in mice are frequently subclonal and heterogenous among different primary TCL1 mice. We further describe that this molecular heterogeneity mirrors heterogenous disease characteristics such as organ infiltration or CLL dependent T cell skewing. Similar to human CLL, we further observed the occurrence of novel mutations and structural variations during clonal evolution and found plasticity in the expansion of B cell receptor specific subclones. Thus, our results uncover that the genetic complexity, pathway dependence and clonal dynamics in mouse CLL are in relevant agreement to human CLL, and they are important to consider in future research using the TCL1 mouse for studying CLL.
Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||
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Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | ||||||||||||||||||||||||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||||||||||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Tumors -- Genetics, Exomes, Physiology, Pathological, Chronic lymphocytic leukemia | ||||||||||||||||||||||||||||||||||||
Journal or Publication Title: | Leukemia | ||||||||||||||||||||||||||||||||||||
Publisher: | Nature Publishing Group | ||||||||||||||||||||||||||||||||||||
ISSN: | 0887-6924 | ||||||||||||||||||||||||||||||||||||
Official Date: | April 2019 | ||||||||||||||||||||||||||||||||||||
Dates: |
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Volume: | 33 | ||||||||||||||||||||||||||||||||||||
Number: | 4 | ||||||||||||||||||||||||||||||||||||
Page Range: | pp. 957-968 | ||||||||||||||||||||||||||||||||||||
DOI: | 10.1038/s41375-018-0260-4 | ||||||||||||||||||||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||||||||||||||||||||
Reuse Statement (publisher, data, author rights): | First published by Nature Group 2018 | ||||||||||||||||||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||||||||||||||
Date of first compliant deposit: | 20 August 2018 | ||||||||||||||||||||||||||||||||||||
Date of first compliant Open Access: | 5 November 2018 | ||||||||||||||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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