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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 TCL1in B cells leads after a long latency to a CLL-like disease in aged Eµ-TCL1mice suggesting that TCL1overexpression 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-TCL1mice. 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-TCL1mice 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-TCL1mouse model for progressive CLL. Among them, a recurrent gain of chromosome 15, where Mycis located, was identified in almost all tumors in Eµ-TCL1mice. Interestingly, amplification of 8q24, the chromosomal region containing MYCin humans, was associated with worse outcome of patients with CLL.

Chronic lymphocytic leukemia (CLL) is associated with substantial alteration in T-cell composition and function. However, the role of T-cells in CLL remains largely controversial. While T-cells can induce pro-survival signals in leukemic cells, there are several indications for existing, yet defective, anti-tumor immune responses in CLL patients. Here, we utilized the Eµ-TCL1 (TCL1) mouse model of CLL to delineate whether anti-tumoral immune responses exist in CLL, and characterize the phenotype and function of these potential anti-tumoral immune populations.

No relevant conflicts of interest to declare.

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that is characterized by apoptosis resistance and dysfunctional immune system. The chronic nature and slow development of the disease indicates a contribution of CLL-induced inflammation in the disease course. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in an in vivosystem. Here, we used the well-established CLL mouse model, Eµ-TCL1 mice (TCL1), to characterize changes within myeloid cell populations along with CLL development and the influence of their depletion on disease progression and immune dysfunction.