Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL

Abstract

Chronic lymphocytic leukemia (CLL) cells require complex microenvironmental and immunologic interactions to survive and proliferate. Such interactions might be best recreated in animal models; however, this needs extensive verification. We therefore investigated the composition of the T-cell compartment in the El-TCL1 transgenic mouse, currently the most widely used murine model for CLL. Immunophenotyping and transplant approaches were used to define T-cell subsets at various stages of CLL. Analogous to human CLL, we observed a skewing of T-cell subsets from naive to antigen-experienced memory T cells that was more pronounced in lymph nodes than in blood. Transplantation of CLL into non-transgenic recipients was feasible without immunosuppression in a pure C57BL/6 background and resulted in the prominent skewing of the T cells of the recipient mice. Both in spontaneously developed CLL and in the transplantation setting, a loss in T-cell receptor diversity was observed, with a relevant number of clonal T-cell populations arising. This suggests that antigen-dependent differentiation toward the T memory pool is initiated by murine CLL cells. In summary, we validate the TCL1 transgenic mouse model for analysis of T-cell phenotypes and suggest a CLL-dependent antigen-driven skewing of T cells in these mice.

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

“…22 The TCL1 mouse was constructed to specifically overexpress the TCL1 gene in B cells using the Em-enhancer promoter system. [22][23][24]30 The mean difference between the expressed Ig V(H) genes of these mice and germ line is only 0.5%, thus the TCL1 mouse is thought to model the more aggressive, IgV(H) unmutated form of the disease in humans. 37 Lymphocytes of TCL1-mice with overt leukemia were engrafted in 10 C57BL/6 mice, as previously described.…”

“…37 Lymphocytes of TCL1-mice with overt leukemia were engrafted in 10 C57BL/6 mice, as previously described. [22][23][24]30 However, two of them died before the start of treatment, indicating that they had advanced tumor progression. The remaining eight mice were equally divided between control (phosphate-buffered saline) and treatment arms (0.06 mg/kg actinomycin D for 14 consecutive days i.p.).…”

“…Furthermore, the efficacy of actinomycin D is tested in two different mouse models for high-risk CLL. [22][23][24][25] …”

Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

“…In an accelerated euTCL1 model, T-cell alterations induced by disease progression were found to be antigen-driven and clonally skewed. 42 McClanahan et al investigated CLL T-cell function in aging and accelerated euTCL1 models.…”

“…Examining the CLL T-cell compartment has resulted in novel mechanisms for CLL progression and interest in immunotherapeutic strategies. [41][42][43] To study the dependence of CLL B cells on immune subsets, carboxyfluorescein succinimidyl ester-labeled human CLL cells were injected into NSG mice alongside various immune components, such as CD34 1 progenitor cells, mesenchymal stromal cells, or mature APCs. 44 Data demonstrated that T cells activated by allogeneic APCs were required for leukemic cell survival and proliferation.…”