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Leukemia. 2019 Apr;33(4):957-968. doi: 10.1038/s41375-018-0260-4. Epub 2018 Sep 27.

Exome sequencing of the TCL1 mouse model for CLL reveals genetic heterogeneity and dynamics during disease development.

Author information

1
Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. n.zaborsky@salk.at.
2
Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg, Austria. n.zaborsky@salk.at.
3
Cancer Cluster Salzburg, Salzburg, Austria. n.zaborsky@salk.at.
4
Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.
5
Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg, Austria.
6
Cancer Cluster Salzburg, Salzburg, Austria.
7
School of Life Sciences, University of Warwick, Coventry, UK.

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 wild-type 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.

PMID:
30262843
PMCID:
PMC6477797
DOI:
10.1038/s41375-018-0260-4
[Indexed for MEDLINE]
Free PMC Article

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