Rosenquist_EU Haematology 03/03/2010 13:22 Page 81
Recurrent Genomic Aberrations in CLL – Implications for Disease Pathogenesis and Prognosis
CLL/lymphoma 2 (BCL2).
BCL2 is commonly found to be Figure 1: Fluorescence In Situ Hybridisation Analysis of
overexpressed in CLL,
and defective apoptosis due to BCL2
del(11q) and del(17p)
overexpression has previously been suggested as an explanation for
why tumour cells accumulate in CLL.
Juliusson et al., on behalf of the International Working Party on
Chromosomes in CLL (IWCCLL), were the first to show the prognostic
significance of 13q14 deletions, where patients carrying this abnormality
appeared to have a favourable prognosis.
This finding has since been
replicated in a number of studies, including a publication from our
In addition, we detected a tendency among patients with a
homozygous deletion of 13q, who account for approximately 20% of
patients with del(13q), to have better clinical outcome compared with
patients with heterozygous deletions only.
This could partly be
explained by a higher frequency of mutated immunoglobulin heavy-
chain variable (IGHV) genes among patients with homozygous deletions
(95%) compared with cases with only one deleted copy of 13q (73%).
However, a recent paper found no significant difference in time to first
treatment (TTT) or overall survival (OS) when studying patients with
heterozygous and homozygous 13q deletions.
Interestingly, the authors
reported an association between the fraction of 13q- nuclei and clinical
outcome, where patients carrying a high percentage of aberrant cells
A chronic lymphocytic leukaemia (CLL) cell (the nucleus is stained blue using 4',6-diamidino-
had a significantly shorter TTT, supporting similar findings in an earlier
2-phenylindole [DAPI]) is analysed using probes directed to ATM in 11q (SpectrumGreen,
This indicates that there is probably more to the 13q- story
green colour) and TP53 in 17p (SpectrumOrange, red colour). Both copies of TP53 are
present, while one copy of ATM is found to be deleted.
than previously believed, and warrants further characterisation.
Deletion of 11q22–q23 identified a partial trisomy 12q in a few cases,
A deletion in the long arm of chromosome 11 is the second most subsequently narrowed down to 12q13–q15, and which contains the
common chromosomal abnormality in CLL, with a frequency that is oncogenic murine double minute 2 (MDM2) gene.
currently estimated to be around 12–18% of all patients
(see as an important feedback regulator of TP53 and has been found to be
Figure 1). The minimal affected region is larger than that of the dysregulated in CLL.
Another candidate gene that has recently
recurrent deletion in 13q and is mapped to a 2–3Mb region.
There been in focus is the CLL upregulated gene 1 (CLLU1), which is located
are several genes defined within this interval, with the ataxia in 12q22.
Interestingly, CLLU1 has been shown to display CLL-specific
telangiectasia mutated (ATM) gene being the most promising expression not detected in normal tissue or in other haematological
candidate. ATM is a key regulator of multiple signalling cascades that malignancies. However, no increase in expression was found in
respond to DNA damage, and has been found to phosphorylate p53, patients carrying trisomy 12.
Similarly, in a protein expression study
thereby triggering the various p53-dependent signalling pathways.
In of other chromosome 12 candidate genes, including CCND2, CDK2,
addition, both deletion and missense mutations of ATM have been CDK4 and STAT6, no difference in expression was demonstrated in
found in T-cell pro-lymphocytic leukaemia and mantle cell cases with or without trisomy 12.
Mutations in ATM have been reported in CLL, where
they are predominantly found in 11q-deleted patients.
Although the exact role of trisomy 12 in the pathogenesis of CLL is
unclear, it has nevertheless been shown to have clinical significance.
The prognostic relevance of 11q deletions in CLL was initially reported in This was initially published at the beginning of 1990s by the IWCCLL,
the mid-1990s, when patients carrying this deletion were shown to have where patients carrying this abnormality were found to have the
progressive disease and reduced survival.
These findings have since shortest survival among all patients with single aberrations.
been confirmed in numerous studies, including a recent publication trisomy 12 is associated with an intermediate survival and short TTT.
from our laboratory.
In multivariate analysis, the presence of 11q
deletion is a significant predictor of clinical outcome.
In addition, Deletion of 17p
patients carrying an 11q deletion often display a distinctive clinical Loss of 17p, which harbours the TP53 gene, is detected in up to 10%
feature characterised by abdominal and mediastinal lymphadenopathy.
of CLL patients, although a higher frequency is reported in
Interestingly, there is recent evidence that chemoimmunotherapy fludarabine-refractory cases.
In addition, the majority of patients
including rituximab may overcome the adverse prognostic significance displaying a 17p deletion also carry mutations on the remaining allele,
of 11q deletion in previously untreated patients with CLL.
whereas only up to 5% of non-17p-deleted cases are TP53-
In CLL, loss of 17p is associated with the worst survival
Trisomy 12 and shortest TTT, as well as treatment failure with purine nucleoside
This recurrent chromosomal abnormality was the first and the most analogues and alkylating agents.
Recent reports have also
commonly detected aberration in the early days of CLL cytogenetics.
shown an independent prognostic value of TP53 mutations without
Trisomy 12 is today detected in 11–16% of all patients with CLL,
the accompanying deletion.
In addition, TP53 abnormalities are
although an early study using FISH on interphase cells reported a further associated with disease transformation to diffuse large B-cell
frequency as high as 35%.
A number of banding studies have lymphoma (Richter’s syndrome).
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