ANIMAL MODELS OF B-CLL
enormous amount of new information has been gleaned by directly studying human
B-CLL cells, animal models are now contributing to our understand-ing of the
human disease. For example, New Zealand Black (NZB) mice spontane-ously
develop, with age, an expansion of IgM+CD5+ 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.
years, however, a variety of transgenic mouse models have been devel-oped that
lead to diseased phenotypes resembling human B-CLL more closely and
reproducibly. We focus on three models that have been especially helpful.
mice expressing the TCL1 gene in
murine B cells develop a poly-clonal expansion of B lymphocytes early in life
that becomes progressively more restricted until a monoclonal population
emerges after about one year in most ani-mals. 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 PI3K-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 overexpression of TCL1
in human B-CLL patients is not uniform.
mouse model that develops features resembling human B-CLL in-volves the overexpression
of two genes: BCL-2 and TRAF2 (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 seen 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.
In the third transgenic model, overex-pression
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, expansions of CD5+ B
cells occur in only 40 percent 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 NF,κB pathway, a pathway known to be
constitutively active in some B-CLL clones.
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 amplifi-cation
in vivo. Such an approach may also make it possible to define and test new
therapeutics to treat this currently incur-able disorder.