Longitudinal analyses of CLL in mice identify leukemia-related clonal changes including a Myc gain predicting poor outcome in patients

Selcen Öztürk,Bola Hanna,Lavinia Arseni,Yashna Paul,Anna Jauch,Philipp M Roessner,Saira Afzal,Irene Gil-Farina,Peter-Martin Bruch,Manfred Schmidt,Marc Zapatka,Sascha Dietrich,Peter Lichter,Martina Seiffert,Verena Kalter,Stephan Stilgenbauer

doi:10.1038/s41375-021-01381-4

Abstract

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy mainly occurring at an advanced age with no single major genetic driver. Transgenic expression of TCL1 in B cells leads after a long latency to a CLL-like disease in aged Eµ-TCL1 mice suggesting that TCL1 overexpression is not sufficient for full leukemic transformation. In search for secondary genetic events and to elucidate the clonal evolution of CLL, we performed whole exome and B-cell receptor sequencing of longitudinal leukemia samples of Eµ-TCL1 mice. We observed a B-cell receptor stereotypy, as described in patients, confirming that CLL is an antigen-driven disease. Deep sequencing showed that leukemia in Eµ-TCL1 mice is mostly monoclonal. Rare oligoclonality was associated with inability of tumors to develop disease upon adoptive transfer in mice. In addition, we identified clonal changes and a sequential acquisition of mutations with known relevance in CLL, which highlights the genetic similarities and therefore, suitability of the Eµ-TCL1 mouse model for progressive CLL. Among them, a recurrent gain of chromosome 15, where Myc is located, was identified in almost all tumors in Eµ-TCL1 mice. Interestingly, amplification of 8q24, the chromosomal region containing MYC in humans, was associated with worse outcome of patients with CLL.

Highlights

Cellular heterogeneity and clonal evolution of tumors are of major interest in the era of targeted therapies, as these likely impact differently on specific cancer clones
Sex-matched recipient mice results frequently in individual these results indicate that different clonal evolution patterns are differences in tumor development, making analysis of treatment observed in different tumors of Eμ-TCL1 mice, which might effects challenging in this model
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy driven by antigenic stimulation of the B-cell receptor (BCR), as well as genetic aberrations affecting different cellular pathways, including RNA processing, DNA damage and cell cycle control, chromatin modifications, Notch and Wnt signaling, and inflammatory pathways [2]

Summary

Introduction

Cellular heterogeneity and clonal evolution of tumors are of major interest in the era of targeted therapies, as these likely impact differently on specific cancer clones. Some tumor clones get reduced, but inadvertently drugs provide potent selective pressure for expansion of other clones, a major cause of therapy resistance [1]. Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells in which genetic driver lesions and their relationship to clonal evolution have been identified [2], and an association of clonal evolution with treatment relapse and drug resistance has been described [3]. Eμ-TCL1 mice are the most accepted and widely used mouse model of CLL for studying disease biology and for preclinical drug testing. This mouse model line was established by exogenous expression of the human TCL1 gene under the control of the immunoglobulin heavy chain variable region (IGHV) promoter and IGH (Eμ) enhancer [4]. Starting from 6 months of age, these mice develop a CLL-like disease characterized by an accumulation of

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