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.
Highlights
Recent high throughput sequencing approaches revealed complex genetic landscapes in multiple human cancer entities [1]
Yellow dots represent mutated genes that roughly correspond to clonal heterozygous somatic mutations within BCR-specific subclone #2. e Same analysis as (d) with primary TCL1 mice transplants descending from TCL1 mouse D22, we found the occurrence of additional mutations with increasing transplantation rounds, indicating significant clonal evolution within the original BCR clone during tumor growth in recipients (Fig. 5)
Mutations complementing TCL1, a driver not universally accepted to be important in human chronic lymphocytic leukemia (CLL), were detected in genes that have not been described in human CLL
Summary
Recent high throughput sequencing approaches revealed complex genetic landscapes in multiple human cancer entities [1]. TCL1 mice exhibit typical T cell skewing associated with CLL development, which is the emergence of TCR-Vβ specific T cell clones and a shift towards effector memory T cells [8, 12,13,14]. It is currently unknown whether specified IGHV rearrangement on the background of TCL1 overexpression is sufficient for leukemogenesis or if additional mutations are acquired during the preleukemic latency period
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