Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3270-3271
CORRESPONDENCE
API1-MALT1/MLT Is Involved in Mucosa-Associated Lymphoid
Tissue Lymphoma With t(11;18)(q21;q21)
 |
LETTER |
To the Editor:
Dierlamm et al1 reported in the June 1 issue of
Blood that an apoptosis inhibitor gene, API2 at 11q21, and a
novel gene, MLT at 18q21, are involved in t(11;18)(q21;q21) associated
with mucosa-associated lymphoid tissue (MALT) lymphoma.1 We
recently reported the results of a breakpoint analysis of an MALT
lymphoma with t(11;18)(q21;q21) by means of fluorescence in situ
hybridization (FISH) analysis using YAC contig at 18q21, which
identified a YAC clone, y789F3, encompassing the breakpoint
region.2 Our further analysis of t(11;18)(q21;q21) with the
YAC clone has identified a novel gene at 18q21, which was found to be
derived from the same gene as the MLT gene.3 This gene was
designated as MALT1 in accordance with the recommendation by the genome
nomenclature committee.
We first would like to point out that there is some confusion regarding
the name of the 11q21 gene. Dierlamm et al1 described the
11q21 gene as API2 in their report, but the sequence shown in their
article represents that of API1 rather than API2 as assessed by the
GenBank registry (GenBank Accession No. NM001165). The other three
names already designated to the 11q21 gene, namely c-IAP2,4
HIAP1,5 and MIHC,6 were correctly used in
Dierlamm's article and, again, the sequence of these genes is
identical to that of API1. We have also confirmed the presence of
API1(c-IAP2)-MALT1/MLT fusion transcripts by using reverse
transcription-polymerase chain analysis (RT-PCR) for our series of MALT
lymphomas with t(11;18) as noted in our report.3 To avoid
any further confusion, we strongly suggest that API2 should be
corrected to API1.
We next would like to point out a few but significant differences
between Dierlamm et al's results1 and ours3
regarding the analysis of the MALT1/MLT gene. In the former, it is
mentioned that the MLT transcript is approximately 3.0 kb and the
predicted MLT protein consists of 729 amino acids (data not shown in
the article).1 Our analysis, on the other hand, indicated
that the MALT1 transcripts are 4.5 kb and 3.1 kb and the open reading frame of MALT1 predicted a protein of 813 amino acids.3 The Northern blot analysis with MALT lymphoma with t(11;18)(q21;q21) demonstrated additional aberrant signals in the range from 6.4 kb to
9.4 kb.3 Furthermore, the deletion of 11 amino acids has
been noted in our MALT1 sequence (API2-MLT amino acids 625 to 635;
GRTDEAVECTE).1,3 In our analysis, 3 out of 5 MALT1 cDNA
clones did not contain the 11 amino acids, whereas the remaining 2 cDNA
clones did (unpublished results, March 1999). We
tentatively chose the cDNA sequence lacking the 11 amino acids for the
MALT1 sequence,3 and consider it most likely that the
difference between the two sequences is due to alternative splicing of
the MALT1/MLT gene. Although the true size of MALT1/MLT amino acids remained to be determined, awareness of the above-mentioned differences should be helpful for readers who plan to perform molecular genetic analysis of the t(11;18) translocation. Further studies are warranted to clarify the essential role of API1-MALT1/MLT fusion protein in the
molecular pathogenesis of MALT lymphomas.
Hiroko Suzuki
Mutsuhito Motegi
Tomoaki Akagi
Yoshitaka Hosokawa
Masao Seto
Laboratory of Chemotherapy
Aichi Cancer Center Research
Institute
Nagoya, Japan
| |
REFERENCES |
1.
Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P:
The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas.
Blood
93:3601, 1999[Abstract/Free Full Text]
2.
Akagi T, Tamura A, Motegi M, Suzuki R, Hosokawa Y, Nakamura S, Morishima Y, Seto M, Taniwaki M:
Molecular cytogenetic delineation of the breakpoint at 18q21.1 in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue.
Genes Chrom Cancer
24:315, 1999[Medline]
[Order article via Infotrieve]
3.
Akagi T, Motegi M, Tamura A, Suzuki R, Hosokawa Y, Suzuki H, Ota H, Nakamura S, Morishima Y, Taniwaki M, Seto M:
A novel gene, MALT1 at 18q21, is involved in t(11;18)(q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue.
Oncogene
18:5785, 1999[Medline]
[Order article via Infotrieve]
4.
Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV:
TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins.
Cell
83:1243, 1995[Medline]
[Order article via Infotrieve]
5.
Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, McLean M, Ikeda JE, MacKenzie A, Korneluk RG:
Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes.
Nature
379:349, 1996[Medline]
[Order article via Infotrieve]
6.
Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL:
Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors.
Proc Natl Acad Sci USA
93:4974, 1996[Abstract/Free Full Text]
Response
There was indeed confusion possible about the nomenclature of the
API1/API2 genes and, therefore, it is useful to summarize the
data. The cloning of API1/API2 was first reported by Rothe et
al,1 who used the names c-IAP1 and c-IAP2.
Liston et al2 independently reported the cloning of the
same proteins named, respectively, hiap-1 and hiap-2.
It should be noted that Hiap-1 corresponds to c-IAP2 and
hiap-2 is identical to c-IAP1, which we think is the
source of the confusion. The same year, Uren et al3 cloned
MIHB and MIHC, which are identical to, respectively, c-IAP1 and c-IAP2. The Genome Database always listed
the following entries: GDB :9848645 
API1 alias
apoptosis inhibitor 1 alias MIHB alias
cIAP1 alias hiap-2 and GDB :9848647 AP12 alias apoptosis inhibitor 2 alias MIHC alias cIAP2 alias hiap-1. We thus propose that the
API2 nomenclature, based on original data and the GDB gene
entries, is followed; consequently the t(11;18) generates an
API2/MLT fusion.
We have obtained from the GDB Gene Nomenclature Committee MLT
as the official gene symbol for the gene on 18q21 involved in the
t(11;18) found in marginal zone B-cell lymphoma of the MALT type. The
t(11;18) breakpoint occurs in different exons of MLT4 (Baens and Marynen, submitted) and we also showed that
differential splicing results in the absence of the GRTDEAVECTE
sequence in the MLT protein derived from 3 out of 11 cDNAs we sequenced
(Baens and Marynen, submitted). Eight cDNAs contained this exon, as
does the EST sequence for clone zq90d12.r1 (GenBank AA214173).
Alternative splicing resulting in different protein isoforms is a
frequent event and we have no functional data allowing to `tentatively choose the cDNA sequence lacking this exon.' As we were
the first to publish the API2/MLT fusion,4 the
MLT symbol was accepted by the Gene Nomenclature Committee and
since there is no reason to assign different gene symbols to different
splice variants of the same gene, we propose that Suzuki et al avoid
any confusion as happened for API1/API2 and consequently adopt
MLT as the gene symbol for the gene involved in the t(11;18).
We performed Northern analyses with the MLT probe on total RNA
and detected a major transcript of 3.0 kb. This transcript must
correspond to the 3.1 transcript of Suzuki et al. These Northern blots
also show a weak band at 4.5 kb. Whether this corresponds to a
transcript identical to the longer one seen by Suzuki et al remains to
be investigated. Similarly, it remains to be investigated whether the
longer open reading frame reported by these authors results from
alternative splicing, the use of a different promotor, or from
experimental differences, and we agree that this could be relevant with
regard to the biology of the MLT protein. In this regard we would like
to point out that we presented evidence for the fact that the relevant
fusion resulting from the t(11;18) is the one generating an
API2-MLT mRNA.4 In fact, data presented by Akagi et
al5 seem to support this claim, as in one of their cases
the t(11;18) is accompanied by a deletion of 18q sequences, which most
probably contains the 5' part of the MLT gene.
Peter Marynen
Mathijs Baens
Human Genome Laboratory
Center for
Human Genetics-Flanders Interuniversitry Institute for Biotechnology
University of Leuven
Belgium
| |
REFERENCES |
1.
Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV:
The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins.
Cell
83:1243, 1995
2.
Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton HG, Farahani R, McLean M, Ikeda JE, MacKenzie A, Korneluk RG:
Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes.
Nature
379:349, 1996
3.
Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL:
Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors.
Proc Natl Acad Sci USA
93:4974, 1996
4.
Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van Den Berghe H, Marynen P:
The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with MALT lymphomas.
Blood
93:3601, 1999
5.
Akagi T, Tamura A, Motegi M, Suzuki R, Hosokawa Y, Nakamura S, Morishima Y, Seto M, Taniwaki M:
Molecular cytogenetic delineation of the breakpoint at 18q21.1 in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue.
Genes Chromosom Cancer
24:315, 1999
