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 after a long latency to a CLL-like disease in aged E mu-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 E mu-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 E mu-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 E mu-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 E mu-TCL1 mice. Interestingly, amplification of 8q24, the chromosomal region containing MYC in humans, was associated with worse outcome of patients with CLL. Clonal evolution and genomic alterations in the E mu-TCL1 mouse model mirror human CLL and identify Myc as oncogenic hit associated with disease progression in patients.

Automated summary

CLL is a B-cell malignancy occurring mainly in the elderly, with transgenic expression of TCL1 not sufficient for full leukemic transformation. Studies using E mu-TCL1 mice showed B-cell receptor stereotypy similar to patients, confirming the antigen-driven nature of CLL. Genomic alterations in E mu-TCL1 mouse model mirror human CLL and identify Myc as an oncogenic hit associated with disease progression in patients.