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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2624-2625
CORRESPONDENCE
To the editor:
Immunoglobulin (Ig)/BCL6 versus
non-Ig/BCL6 gene fusion in diffuse large B-cell lymphoma
corresponds to a high- versus low-level expression of BCL6
mRNA
We read with interest the manuscript of Lossos et
al,1 in which they disclosed the impact of BCL6
mRNA expression on the clinical outcome of diffuse large B-cell
lymphoma (DLBCL). The authors established a quantitative real-time
polymerase chain reaction (PCR) method using TaqMan technology to
measure the levels of BCL6 mRNA in clinical materials. They
first analyzed 22 cases of DLBCL and found that the overall survival
(OS) of patients with high BCL6 expression was significantly
superior to that of patients with low BCL6 expression, and
their finding was validated in an additional 39 cases. They suggested
that high BCL6 mRNA expression is a new favorable prognostic
factor for DLBCL. 3q27 translocation affecting BCL6 gene has been observed in
20% to 40% of DLBCL.2 The particular feature of
BCL6 translocation is that it can involve not only either
one of the 3 immunoglobulin genes (Ig) but also another
non-Ig partner.2,3 Our initial study suggested
that DLBCL cases with non-Ig/BCL6 translocation showed a worse prognosis than those with
Ig/BCL6.4 In an updated comparison between 17 cases with non-Ig partners, including 2 with a deletion of a
larger than 1-kb segment encompassing the BCL6 exon
1, and 26 cases with Ig partners, OS of the former group was
inferior to that of the latter group (P = .0400). Thus, we propose that the non-Ig/BCL6 fusion gene is a poor
prognostic indicator of DLBCL. To test the correlation between the 2 independent studies on the
prognostic significance of BCL6, we compared the levels of BCL6 mRNA between DLBCL cases with Ig/BCL6
translocation and those with non-Ig/BCL6. Total cellular RNA
were prepared from cryopreserved tumor cells and subjected to real-time
PCR analysis using an ABI Prism 7700 Sequence Detection System (PE
Applied Biosystems, Foster City, CA). The sequences of oligonucleotide
primers as well as the fluorogenically labeled probe were as
described.1 The amount of BCL6 mRNA of test
materials was divided by that of the endogenous reference, the
glyceraldehydes-3-phosphate dehydrogenase gene (GAPDH), and
the BCL6-GAPDH values were further normalized
with that of Raji cells.1 As indicated in Figure
1, the comparison study clearly showed
that BCL6 mRNA levels of the Ig/BCL6 group (n = 6; range, 2.2-7.0; mean, 4.3) were significantly higher than those of the non-Ig/BCL6 group (n = 8; range, 0.4-1.9;
mean, 1.0) (P = .0003). In contrast, the values of DLBCL
cases that lacked BCL6 rearrangement were distributed from
1.2 to 10.7 (n = 9; mean, 6.5). We next performed reverse
transcriptase-mediated PCR using a forward primer for BCL6
exon 1 and a reverse primer for exon 4. There were no measurable
amounts of normal BCL6 transcripts in cases with
BCL6 translocation, though additional PCR using nested
primer sets generated PCR products in a proportion of the materials
tested. It is therefore likely that the observed BCL6 mRNA
in both Ig/BCL6 and non-Ig/BCL6 cases represented
transcription not of the normal BCL6 but of the rearranged
BCL6 allele.
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| Figure 1.
BCL6 mRNA expression levels in lymphoma cells determined by real-time
PCR.
The BCL6/GAPDH ratio of each test material was
normalized by that of Raji ( = 1). Cell lines: Ramos, a Burkitt
lymphoma cell line with t(8;14)(q24;q32); FL-18 and FL-218, follicular
lymphoma cell lines with t(14;18)(q32;q21); YM, a DLBCL cell line with
t(3;16)(q27;p11)6; HBL-2 and KIS-1, DLBCL cell lines with
t(11;14)(q13;q32) and t(9;14)(p13;q32), respectively. Clinical
materials of DLBCL: DLBCL with Ig/BCL6
translocation, n = 6; DLBCL with non-Ig/BCL6
translocation, n = 8; other DLBCLs lacking BCL6
translocation, n = 9. Horizontal bars indicate the mean values of
each group.
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DLBCL is a heterogeneous subcategory of non-Hodgkin lymphoma in
terms of cell morphology, immunophenotype, and genetic abnormality. Many studies have focused on whether these parameters are associated with particular clinical features and the treatment outcome of DLBCL.5 Lossos et al1 and our own
studies,4 including this report, suggest that
Ig versus non-Ig partner of BCL6
translocation and high versus low BCL6 mRNA expression are
both prognostic indicators of DLBCL, potentially reflecting a role of
BCL6 in the pathogenesis of DLBCL. We very recently found
that t(3;16)(q27;p11) translocation leads to the fusion of
BCL6 with the interleukin-21 receptor gene (IL-21R).6 Although IL-21R was
actively transcribed in a DLBCL cell line (YM) carrying this particular
non-Ig/BCL6 translocation, the level of BCL6
mRNA, which was under the control of IL-21R promoter, was
unexpectedly low (Figure 1). Thus, it is possible that BCL6
expression is down-regulated in lymphoma cells with t(3;16) once the
cells have obtained a malignant phenotype. In contrast, lymphoma cells
with Ig/BCL6 may show a persistent expression of
BCL6 at higher levels, corresponding to a feature of
germinal center B-like DLBCL.7 Further studies are needed
to elucidate the mechanistic detail involved in the transcriptional
control of BCL6 in lymphoma cells.
Chiyoko Ueda, Takashi Uchiyama, and Hitoshi Ohno
Correspondence: Hitoshi Ohno, First Division, Department of
Internal Medicine, Faculty of Medicine, Kyoto University,
54-Shogoin-Kawaramachi, Sakyo-ku, Kyoto 606-8507, Japan; e-mail:
hohno{at}kuhp.kyoto-u.ac.jp
References
1.
Lossos IS, Jones CD, Warnke R, et al.
Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma.
Blood.
2001;98:945-951[Abstract/Free Full Text].
2.
Ohno H, Fukuhara S.
Significance of rearrangement of the BCL6 gene in B-cell lymphoid neoplasms.
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3.
Akasaka H, Akasaka T, Kurata M, et al.
Molecular anatomy of BCL6 translocations revealed by long-distance polymerase chain reaction-based assays.
Cancer Res.
2000;60:2335-2341[Abstract/Free Full Text].
4.
Akasaka T, Ueda C, Kurata M, et al.
Nonimmunoglobulin (non-Ig)/BCL6 gene fusion in diffuse large B-cell lymphoma results in worse prognosis than Ig/BCL6.
Blood.
2000;96:2907-2909[Abstract/Free Full Text].
5.
Kramer MH, Hermans J, Wijburg E, et al.
Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma.
Blood.
1998;92:3152-3162[Abstract/Free Full Text].
6.
Ueda C, Akasaka T, Kurata M, et al.
The gene for interleukin-21 receptor is the partner of BCL6 in t(3;16)(q27;p11), which is recurrently observed in diffuse large B-cell lymphoma.
Oncogene.
2002;21:368-376[CrossRef][Medline]
[Order article via Infotrieve].
7.
Alizadeh AA, Eisen MB, Davis RE, et al.
Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.
Nature.
2000;403:503-511[CrossRef][Medline]
[Order article via Infotrieve].
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