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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.

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