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

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 to the development of a CLL-like disease in aged Eµ-TCL1 mice modelling the human disease in many aspects. The long latency of leukemia development in these mice suggests that although TCL1 overexpression is the initial factor, it 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 the Eµ-TCL1 mouse model. 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 engraft and 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.