Rosenquist_EU Haematology 03/03/2010 13:23 Page 82
Haematological Malignancies Lymphoproliferative Disorders
Figure 2: Genomic Profile of a Chronic Lymphocytic Leukaemia Patient Using a
High-density Single-nucleotide Polymorphism Array
0.5
t
i
o
0.15
ra
2
0
Log
-0.15
-0.5
1 3 5 7 9 11 13 15 17 19 21 X
2 4 6 8 10 12 14 16 18 20 22 Y
Chromosomes
Deletions are detected in 6q, 8p, 13q, 17p and 18p, while a gain is identified in 8q.
The current agents used in chemotherapy aim to interrupt the cell Translocations Involving the
cycle or induce apoptosis through the p53 pathway, which in this Immunoglobulin Heavy-chain Locus
group of patients is rendered non-functional.
65
Treatment with high- Recent advances in cultivation techniques, including stimulation of CLL
dose methylprednisolone, a glucocorticoid that acts independently of cells with CpG oligonucleotides, interleukin 2 (IL-2) and CD40L, have
the p53 pathway, has been shown to be effective in patients with resulted in an improved ability to detect chromosomal aberrations
p53 defects.
66
In addition, alternative treatment with the anti-CD52 using conventional cytogenetics.
80–82
As a result, chromosomal
monoclonal antibody alemtuzumab, which acts via complement- translocations that previously were thought to be rare events in CLL
dependent cytotoxicity and antibody-dependent cell-mediated are now detected in more than 30% of patients.
11,83,84
In addition, the
cytotoxicity, has shown promising results.
67–69
Finally, refractory patients presence of translocations, both balanced and unbalanced, was
who are deemed to be physically fit, particularly younger patients, may associated with poor clinical outcome.
83,85
However, translocations are
be considered for allogeneic stem cell transplantation.
70
detected primarily as non-recurrent events. The most commonly
affected region (detected in 27% of all translocations and 5% of all
In multivariate analysis of prognostic markers in CLL, deletion of 17p cases) involves the immunoglobulin heavy-chain (IGH) locus on
has repeatedly been shown to be one of the strongest independent 14q32.
11
Chromosomal translocations involving the IG loci are found in
markers of clinical outcome.
6,7
Loss of 17p is most commonly many B-cell malignancies. These chromosomal rearrangements led to
associated with other poor prognostic markers, such as unmutated the dysregulation of oncogenes by juxtaposition to the IG loci. In CLL,
IGHV genes and advanced Binet stage.
6
However, a recent study by patients carrying translocations involving the IGH locus identify a
Best et al. reported a subset of CLL patients with TP53 abnormalities disease subset with poor prognosis.
86
and mutated IGHV genes having stable disease for several years
without any need for therapy.
71
We have found similar results in our t(14;18)(q32;q21)–BCL2
laboratory (unpublished data). Thus, 17p abnormalities do not Although characteristic of follicular lymphoma (FL), where this
necessarily result in poor prognosis, and there seems to be a translocation involving BCL2 is observed in approximately 90% of
subgroup of patients who do not require treatment. This finding may cases, this rearrangement has also been shown in CLL.
83,87,88
BCL2 is
argue against early introduction of chemotherapy in 17p-deleted overexpressed in several lymphoid malignancies, including CLL.
21,22,89
patients without any clinical symptoms. Interestingly, in FL the breakpoint in chromosome 18 occurs primarily
at the 3’ end of BCL2, while in CLL the break tends to occur at the 5’
Deletions of 6q end of the same gene, juxtaposing BCL2 to the IG light chains.
77
Structural alterations in the long arm of chromosome 6 are
commonly found in lymphoid malignancies.
72,73
In CLL, a minimally t(14;19)(q32;q13)–BCL3
deleted region has been defined in 6q21, and is reported in 6–7% of The translocation involving the IGH and the BCL3 gene loci are present
cases.
74,75
In addition, a second recurrent deletion has been shown in various B-cell malignancies. They are most commonly found in CLL,
in 6q27.
75,76
So far, no genes involved in the pathogenesis of CLL where they are also associated with poor prognostic markers such as
have been indicated for this region; however, absent in melanoma additional chromosomal changes, including trisomy 12 and unmutated
1 (AIM1) has been suggested as a candidate gene.
12,74,77
Although IGHV genes.
90
In addition, this translocation has been reported primarily
several studies showed deletions in 6q to be associated with higher in patients carrying IGHV4-39/IGHD6-13/IGHJ5 rearrangements.
90
white blood cell counts and more extensive lymphadenopathy,
which may serve as a marker of progression, the prognostic value Novel Recurrent Aberrations
of this structural aberration remains unclear due to conflicting The application of high-density single-nucleotide polymorphism (SNP)
reports.
75,78,79
We did not detect any deletions in 6q in a cohort of arrays for evaluation of genomic aberrations in CLL has in recent years
newly diagnosed CLL patients, which argues for this deletion as a resulted in the detection of several new recurrent abnormalities. These
marker of progression.
13
abnormalities include gain of 2p and 8q and deletion of 4p, 8p and 22q,
82
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