PART ONE
General Cytology
Fig. 2.12 Karyotype
showing a t(8;14)(q24;q32)
chromosomal translocation (arrows) characteristic
of
Burkitt's lymphoma
(or ALL L3). Segmental
duplication of chromosome 1q and loss of
chromosome 17p are recurrent additional
chromosome aberrations in this type of
lymphoma.
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restricted to B cells in the GC. In contrast, the heterologous
Ig
and non-Ig promoters exhibit a broader spectrum of activity in
B-cell ontogenetic stages and will prevent
BCL6
downregulation
in post-GC cells. A block in the normal downregulation of
BCL6
might thus favor differentiation arrest, continuous cell prolifera-
tion, survival, and genetic instability, all of which allowing neo-
plastic transformation. Indeed, the 3q27/BCL6 rearrangement
is sufficient in itself to produce lymphoma as demonstrated by
transgenic mice studies. In addition and independently of
BCL6
translocations, point mutations and small deletions of
BCL6
have been reported in approximately 70% of DLBCL, leading
also to its deregulated expression.35
The clinical relevance of
BCL6
gene translocations has been
initially a subject of controversy with studies reporting improved
survival in patients with
BCL6
translocation, and other failing to
show any statistically significant impact of such rearrangements
on the clinical outcome of DLBCL.36 More recently, a cDNA
microarray analysis demonstrated that DLBCL patients with the
germinal center B-cell-like (GCB) gene expression profile had a
better overall survival than those with the activated B-cell-like
(ABC) expression pattern.37 As
BCL6
is a marker of the GCB-type
signature, its mRNA and protein levels were correlated to clinical
outcome of DLBCL patients: high-level expression of
BCL6
was
associated with significantly longer overall survival and shown
to be a predictor of a favorable treatment outcome in cases of
DLBCL.36
In some cases, 3q27/BCL6 translocation coexists with other
translocations in a single clone, including t(14;18)(q32;21) and
t(8;14)(q24;q32), involving
BCL2
and
c-MYC
oncogenes, respec-
tively. This coexistence of two to three chromosomal transloca-
tions seems not necessarily to have a significant impact on the
clinical features.38 Finally, it must be added that around 20% of
DLBCL exhibit a t(14,18)(q32;q21) similar to that associated
with follicular lymphoma and mutually exclusive of BCL6
rearrangements.
Burkitt's Lymphoma
Burkitt's lymphoma (BL) and its leukemic equivalent, the L3
variant of acute lymphoblastic leukemia, are characterized in
nearly 90% of cases by a reciprocal chromosomal translocation
that juxtaposes the
c-Myc
oncogene (chromosome 8q24) to one
of the immunoglobulin genes located on chromosome 14q32
(IgH),
chromosome 22q11 (IgA), or chromosome 2p12
(IgK)
(Fig. 2.12). All three chromosomal translocations lead to over-
expression of the
c-Myc
gene product.
C-Myc
gene is a transcrip-
tion factor that regulates a very large number of genes through
heterodimerization with the partner protein Max.39 The genes
targeted by the c-Myc/Max heterodimer complexes are involved
in cell proliferation, differentiation, and apoptosis. Such global
transcriptional regulatory function may explain why c-Myc over-
expression is sufficient in itself to promote lymphoma diseases
as demonstrated in transgenic mice studies.
The so-called "Burkitt-like" form is characterized by three
cytogenetic categories: one with an 8q24/
c-MYC
translocation, a
second with associated 8q24/c-MYC and 18q21/BCL2 transloca-
tions, and a third with miscellaneous rearrangements, frequently
including an 18q21/
BCL2
chromosomal translocation.
Recurrent chromosome aberrations associated with the 8q24
translocations include duplications of the 1q21q25 chromo-
somal region, 6q11q14 and 17p chromosomal deletions, and
trisomies for chromosomes 7, 8, 12, and 18. A recent cytoge-
netic and CGH study on BL has demonstrated that the presence
of abnormalities on chromosome 1q (demonstrated either by
cytogenetics or by CGH) and gains of 7q (ascertained only by
CGH) were associated with adverse prognosis.40
Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphoma is a CD30+ T-cell NHL that can
be divided in two majors groups according to the WHO clas-
sification: (1) systemic nodal ALCL and (2) primary cutaneous
ALCL. As this latter group does not exhibit specific chromo-
somal alteration, it will not be pursued further in this review. In
this section, we will only focus on systemic nodal ALCL, more
particularly on anaplastic lymphoma kinase-positive ALCL
where a characteristic t(2;5)(p23;q35) translocation is observed
in approximately 60% of cases. This translocation fuses the
nucleophosmin
(NPM)
gene on chromosome 5q35 to the
ALK
gene on chromosome 2p23, leading to the
NPM-ALK
chimeric
34
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