Biology Reference
In-Depth Information
genome instability.
81
Individuals with AT have a mark-
edly greater propensity (~200-fold) to develop leuke-
mias and lymphomas, with the majority of
malignancies being of T-cell origin, than the general
population.
213
AT children tend to develop T-cell acute
lymphoblastic leukemia, while young adults develop
T-cell prolymphocytic leukemia. T-cells in AT patients
display a very high level of cytogenetic abnormalities,
often involving chromosomes 7 and 14. The transloca-
tions, caused by incorrect rejoining during V(D)J recom-
bination, can result in the juxtaposition of an
immunoglobulin or T-cell receptor (TCR) locus with
the
TCL1
proto-oncogene.
214
Clonal expansion of these
T-cells together with additional cytogenetic abnormali-
ties can give rise to the lymphoid tumors seen in AT
patients.
Nijmegen breakage syndrome, the autosomal reces-
sive disorder associated with mutation of
NBS1
(nibrin),
shares certain similarities to AT, such as immunodefi-
ciency, chromosomal rearrangements and sensitivity to
IR.
215
In addition, NBS patients commonly have
a distinct facial appearance and microcephaly. Like
AT, NBS patients are cancer-prone. More than 40% of
individuals with NBS will develop cancer by the age
of 21. The majority of malignancies are lymphomas,
especially large B-cell non-Hodgkin's lymphoma,
lymphoblastic anaemia, and Hodgkin's lymphoma.
216
Solid tumors are observed less frequently, including
medulloblastoma and rhabdomiosarcoma of the peria-
nal region.
216
Similar to AT, translocations are observed
that result in immunoglobulin gene or
TCR
fusions.
217
Ataxia telangiectasia-like disorder (ATLD), which
results from hypomorphic mutations in the Mre11
protein, shares similar characteristics to AT, including
cerebellar ataxia, heightened radiosensitivity and chro-
mosomal translocations in peripheral blood cells
involving chromosomes 7 and 14.
218
However, to date
there have been no reports of lymphoid malignancies,
but lung adenocarcinoma was observed in two young
brothers with ATLD.
219
Autosomal recessive disorders due to hypomorphic,
and in some instances null, mutations of genes involved
in the NHEJ machinery
DNA-PKcs
,
Artemis
,
Lig4
and
XLF
have recently been identified.
123,220
Individuals
with null and hypomorphic mutations are immunodefi-
cient and cell lines derived from these patients display
pronounced radiosensitivity due to diminished DNA
repair. The severity of immunodeficiency can reflect
null vs hypomorphic mutations, so, for example, null
mutations of
Artemis
lead to complete absence of B
and T lymphocytes, while hypomorphic mutations
display only partial B and T-cell deficiency.
221
A predis-
position to lymphoid cancers has been reported, but
only in individuals with hypomorphic mutations
because the complete loss of B and T-cells seen with
null mutations precludes the development of lymphoid
malignancies.
221
However, because these disorders are
so rare it has not been possible to make further
generalizations regarding their clinical and cellular
phenotypes.
Several groups have taken advantage of the opportu-
nity afforded by the generation of knockout mice to
study the biological effects of lack of specific NHEJ
proteins. An additional benefit of this approach is the
capacity to examine the influence of other genes such
as the tumor suppressor
p53
through the generation of
double knockouts. The phenotypes of several NHEJ
knockout mice are summarized in
Table 8.1
. The mice
share many common features, including enhanced
radiosensitivity (either in the whole animal or in embry-
onic fibroblasts), compromised B and T-cell develop-
ment and impaired V(D)J recombination giving rise to
severe combined immunodeficiency (SCID). In terms
of tumor development, some of the NHEJ knockout
strains, i.e.
Ku70-/-
,
Ku80-/-
, and
DNA-PKcs-/-
, display
a modest predisposition to develop lymphomas. The
principal reason for the lack of a more pronounced
tumor-bearing phenotype is that failure to repair the
DSBs in these NHEJ-deficient strains leads to p53-
dependent cell death. This is most marked in the
XRCC4-/-
and
Lig4-/-
strains, and accounts for their
late embryonic lethality. All the
NHEJ p53-/-
double
knockouts, except the
XLF-/- p53-/-
strain, rapidly
develop pro-B-cell lymphomas. (The single knockout
p53-/-
mice tend to develop T cell lymphomas much
later.) How these pro-B-cell lymphomas arise has been
determined at the molecular level.
222
e
224
The two main
features are the amplification of the
c-myc
oncogene
and immunoglobulin heavy chain (
IgH
) due to chromo-
somal translocation, which probably result from unre-
paired DSB undergoing replication and fusion.
Importantly, these tumors require the V(D)J endonu-
clease, Rag-1, which implies that the DSBs are initially
introduced by this enzyme. The other frequently
observed tumor in the
NHEJ p53-/-
double knockouts
is medulloblastoma, a cerebral tumor originating from
immature neurons. The formation of medulloblastoma
in these mice is independent of Rag-1, suggesting that
the DSBs responsible for the translocations found in
the medulloblastomas arise from endogenous non-
specific DNA damage.
NHEJ Deficiency and Sporadic Tumors
The discussion above makes it clear that NHEJ
proteins protect against tumor induction, but this is in
the context of individuals with complete or near
complete absence of the proteins due to autosomal
recessive disorders or deliberate gene disruption. The
most common tumors are of lymphoid origin because
