Finally, transfer of human B-CLL cells into immune-deficient mice may bypass the ex vivo apoptosis tendency of B-CLL cells, enabling their survival and amplification in vivo. Such an approach may also make it possible to define and test new therapeutics to treat this currently incurable disorders.
In the third tramsgenic model, overexpression of APRIL (a proliferation inducing ligand ) in murine T cells leads indirectly to B-cell proliferation and survival because of signaling through its receptors BCMA and TACI. Unlike the previous two transgenic animals, however, expansion of CD5 B cells occur in only 40% of animals, with these B cells locating predominantly in the spleen and rarely passing into the blood. Nevertheless, as APRIL’s action involves the TRAFs and leads to NFκB activation, this model may prove helpful in linking signals from soluble ligands and surface receptors to the NFκB pathway, a pathway known to be constitutively active in some B-CLL clones.
Another mouse model that develops features resembling human B-CLL involves the overexpression of two genes: BCL-2 and TRAFT2 (TNF-receptor-associated factor 2). This double transgenic animal is especially intriguing because of the already mentioned recent work showing that the deletion at 13q14, often see in human B-CLL, involves the loss of micro-RNAs 15a and 16-1, which affects expression of BCL2. As with the TCL1 transgenic mice, these animals develop CD5 B-cell clones, eventually with massive splenomegaly and leukemia.
Transgenic mice expressing the TCL1 gene in murine B cells develop a polyclonal expression of B lymphocytes early in life that becomes progressively more restricted until a monoclonal population emerges after about one year in most animals. The genetic and phenotypic features of this murine leukemia resemble those of the aggressive, treatment-resistant cases of human U-CLL. Although it is of interest that TCL1 is an activator of the P13K-Akt oncogenic signaling pathway, a pathway not infrequently active in human CLL, the extent to which overexpression of this gene leads to human B-CLL remain to be elucidated, as an over expression of TCL1 in human B-CLL patients is not uniform.
In recent years, however, a variety of transgenic mouse models have been developed that lead to diseased phenotypes resembling human B-CLL more closely and reproducibly. We focus on three models that have been especially helpful.
ANIMAL MODELS OF B-CLL
While an enormous amount of new information has been gleaned by directly studying human B-CLL cells, animal models are now contributing to our understanding of the human disease. For example, New Zealand Black (NZB) mice spontaneously develop, with age, an expansion of IgMCD5 B cells that resembles B-CLL. However, because frank leukemia occurs randomly in only a minor subset of animals, this model has been used sparingly.
Because in vitro observations demonstrate the absence of lesions in the major apoptotic pathways, the model posits the absence of an intrinsic cell death defect in the majority of the leukemic clones. We do not rule out the possibility that developing genetic alterations in the evolving clone can tip the balance between pro- and anti- apoptotic molecules in such a way as to favor B-CLL cell survival. However, the influence of external signals appears to dominate based on current knowledge. This is in line with the in vivo labeling studies indicating the dynamic nature off CLL clones.