The Eµ-TCL-1 mouse model of chronic lymphocytic leukemia

Background: Chronic lymphocytic leukemia (CLL) is a heterogenous disease characterized by the accumulation of CD5+/CD19+ B cells in all lymphoid compartments. Apart from hematopoietic stem cell transplantation, current treatment options are not curative, and in many patients, the disease eventually relapses or becomes resistant to standard therapies. Freclinical evaluation of novel therapeutic approaches for CLL has been limited by the our inability to propagate patient samples in in vitro culture for prolonged periods and the lack of representative cell lines or mouse models. Croce et al. developed and characterised the Ek-TCL-1 mouse model, where the oncogene TCL-1 is overexpressed in B cells, as a putative CLL model. The aim of our studies is to further characterise the mouse model using next-gen sequencing approaches. Materials and Methods: Next-geri sequencing was performed using RNA isolated from CD5+/CD19 cells from the spleens of transgenic mice. We compared the transcriptome profiles of murine leukemic cells with normal B cell subsets and a cohort of human CLL patients (Ferreira et al., 2014). Results: We show that the molecular signatures derived from CD517CD1 9+ leukemic cells from ER-TCL-1 mice are distinct from other normal B cell subsets. Strikingly, molecular signatures of these leukemias demonstrate minimal overlap with those of the those of most human population (Ferreira et al., 2014). Nonetheless, more stringent analysis revealed that the mouse model does bear a close resemblance to a subgroup of human CLL characterized by high TCLI expression. TCL1 overexpression has been associated with adverse outcome in CLL patients. Interestingly, unlike prototypical CLL disease, dysregulation of BCL-2 family protein expression was not detected in leukemic cells from Et-TCL-1 transgenic mice, which appear refractory to the inhibition of BCL2, at least in vitro. Moreover, the leukemias isolated from sick mice showed a surprisingly wide range of sensitivity to standard-of-care agents such as fludarabine. Conclusions: Taken together, our studies suggest that the leukemias which develop in ER-TCL-1 transgenic mice represent a highly aggressive, chemorefractory subtype of CLL. The goals of our ongoing studies are to further characterize this model of CLL and utilize it to test novel therapeutic approaches for treating CLL, particularly chemorefractory disease.