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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3479-3482
BRIEF REPORT
Loss of a novel tumor suppressor gene locus at chromosome 8p is
associated with leukemic mantle cell lymphoma
Jose A. Martinez-Climent,
Esperanza Vizcarra,
Dolors Sanchez,
David Blesa,
Isabel Marugan,
Isabel Benet,
Françesc Sole,
Francisca Rubio-Moscardo,
Maria J. Terol,
Joan Climent,
Elena Sarsotti,
Mar Tormo,
Enrique Andreu,
Marta Salido,
Maria A. Ruiz,
Felipe Prosper,
Reiner Siebert,
Martin J. S. Dyer, and
Javier García-Conde
From the Department of Hematology and Medical Oncology,
Hospital Clínico, University of Valencia, Spain; Laboratory of
Hematologic Cytology, Department of Pathology, Hospital del Mar,
Barcelona, Spain; Section of Hematology, Gandia Hospital, Gandia,
Spain; Institute of Human Genetics, University Hospital Kiel,
Germany; and Department of Haematology, University of Leicester, United
Kingdom.
 |
Abstract |
Patients with mantle cell lymphoma (MCL) may present with either
nodal or leukemic disease. The molecular determinants underlying this
different biologic behavior are not known. This study compared the
pattern of genetic abnormalities in patients with nodal and leukemic
phases of MCL using comparative genomic hybridization (CGH) and
fluorescence in situ hybridization (FISH) for specific gene loci.
Although both leukemic and nodal MCL showed similar genomic patterns of
losses (involving 6q, 11q22-q23, 13q14, and 17p13) and gains (affecting
3q and 8q), genomic loss of chromosome 8p occurred more frequently in
patients with leukemic disease (79% versus 11%,
P < .001). Subsequent CGH analysis confirmed the genomic
loss of 8p21-p23 in 6 of 8 MCL cell lines. Interestingly, MYC gene amplification was restricted to cases with 8p
deletion. These data indicate the presence of a novel tumor suppressor
gene locus on 8p, whose deletion may be associated with leukemic
dissemination and poor prognosis in patients with MCL.
(Blood. 2001;98:3479-3482)
© 2001 by The American Society of Hematology.
| |
Introduction |
Mantle cell lymphoma (MCL) is characterized by the
translocation t(11;14)(q13;q32) resulting in overexpression of cyclin
D1.1-3 Patients with MCL present frequent extranodal
disease at diagnosis, with peripheral blood (PB) involvement observed
in one third of the cases. However, the natural history of MCL
eventually includes involvement of the PB in almost all
cases.1-4 Leukemic MCL has been associated with a worse
prognosis than nodal MCL,4 although a small percentage of
patients with leukemic disease may have an indolent
course.1,5 Although many genetic aberrations in addition
to the t(11;14)(q13;q32) have been correlated with specific features of
the disease, whether these abnormalities are different in the leukemic
and in the nodal forms of MCL remains unknown.5-11 To
address this issue we have compared the pattern of secondary genetic
abnormalities in patients with leukemic and nodal MCL, as well as in 8 MCL-derived cell lines.
| |
Study design |
Twenty-eight patients with MCL with t(11;14)(q13;q32) or
BCL1-IGH gene rearrangement or both, fulfilling the World
Health Organization criteria,3 were diagnosed between 1995 and 2000 among 400 consecutive patients newly diagnosed with B-cell
lymphoproliferative disorders. Histologic, immunophenotypic, cytologic,
and cytogenetic studies were performed in all cases. Screening for
BCL1-IGH gene rearrangement by dual-color fluorescence in
situ hybridization (FISH) and polymerase chain reaction (PCR) assays
were performed in all patients with a suspected MCL.12,13
Among 28 patients diagnosed with MCL, 19 presented with PB involvement
at diagnosis (defined as > 10% CD5/CD19+ cells in the
PB), and 9 patients were classified as having nodal MCL. One nodal and
6 leukemic cases were classified as blastoid variants of MCL (Table
1). Six MCL-derived cell lines (Granta 519, NCEB-1, HBL2, SP-49, REC1, and Z-138), the JVM-2 cell line derived
from a prolymphocytic leukemia, and the SKMM2 cell line derived from a
multiple myeloma, both carrying t(11;14)(q13;q32), were also included
in the study.14 References for the derivation of these
cell lines may be obtained on request.
Comparative genomic hybridization (CGH) and FISH for the presence of
trisomy 12 and deletions of 13q14 (D13S25 locus) and of P53
gene in 17p13 were performed in all patients at diagnosis; the cell
lines were analyzed by CGH and cross-species color banding (RxFISH).
The probes and methods used have been previously
reported.13,15-17 In leukemic cases, studies were
performed on samples from PB or bone marrow (BM) (n = 14), lymph node
(n = 3), and spleen (n = 2), whereas all nodal cases were studied
on lymph node samples. In selected cases and cell lines with genomic
imbalances affecting specific gene loci, the number of copies of
MYC gene (using previously reported probes17),
and ATM and BCL2 genes was determined by FISH
using probes obtained from Dr M. Rocci (University of Bari, Italy,
www.bioserver.biologia.uniba.it).
| |
Results and discussion |
Table 1 shows the cytogenetic, FISH, and CGH studies in the
patients with leukemic MCL (no. 1-19) and nodal MCL (no. 20-28). Those
with leukemic disease showed genomic imbalances in 18 of 19 cases
(95%), with losses being more frequent than gains (88 versus 50). The
median number of chromosomal imbalances per case was 6 (range, 0-18).
High-level amplifications were observed in 7 regions (Xp22, Xq25, 3p25,
18p11, 18q21, 19p, and 19q). The most frequent abnormalities included
gains of 3q (37%), 8q affecting MYC gene (32%), 9q (26%),
Xq (21%), and 15q (16%), and losses of 8p (79%), 13q encompassing
D13S25 locus, 6q and Xp (32%), and 1p22, 11q involving ATM
gene and 17p involving P53 gene (26%). Eight of the 9 patients with nodal MCL displayed chromosomal imbalances, showing a
spectrum of abnormalities similar to that of leukemic MCL and
consistent with previous reports.8-10 (Table 1 and Figure 1A). Nevertheless, the genomic loss of 8p
was associated with the leukemic forms because it was detected in 15 of
19 patients with leukemic MCL (79%) but in only 1 of 9 patients with
nodal MCL (11%; P < .001). Comparison of cases with the
deleted region allowed narrowing of the commonly deleted segment to
8p21-p23 (Figure 1B). Recent studies have reported this genetic
abnormality in patients with human malignancies including T-cell
prolymphocytic leukemia, and bladder, breast, head and neck, prostate,
lung, and colorectal carcinoma.18 However, it has only
been described in 13 of 99 reported cases of MCL studied by
CGH,8-10 and very rarely in other B-cell
lymphomas.11,15,18,19 It has been suggested that a tumor
suppressor gene (TSG) may be located in the subtelomeric region of
chromosome 8p, and associated with increased ability to metastasize in
hepatocellular carcinoma.20 Our results suggest that the
deletion of 8p may be a characteristic molecular marker of leukemic MCL
and that this region may contain a novel TSG with a possible role in
blood dissemination of MCL. Moreover, the loss of 8p was found in all 9 cases with aggressive variants of leukemic MCL (both blastoid and
large-cell subtypes) but in 60% of cases of typical morphology,
suggesting a correlation with aggressive tumors. Because of the
location of the relevant segment at the subtelomeric region of 8p, the
deletion was identified by cytogenetics only in 4 of the 16 patients
with the genomic loss. This may probably explain why this abnormality
has been identified only rarely in previous series of
MCL.8-11,18,19 Additionally, most of our cases were studied
on BM/PB samples, and this may have also contributed to these results.
Interestingly, we found a high incidence of MYC
amplification (6 of 19 cases, 32%), and all these abnormalities were
detected in patients with deletion of 8p. All of them presented with
aggressive MCL; 3 cases were blastoid variants and 3 were classified as
large-cell variants of MCL showing circulating transformed blastlike
cells.21 Confirming previous studies, a tetraploid
karyotype with a double BCL1-IGH gene fusion, or a
simultaneous genomic gain affecting to BCL1 and
IGH loci at 11q13 and 14q32, respectively, was seen in 5 of the 7 blastoid variants, but not in any typical
case.19
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| Figure 1.
Chromosomal imbalances and genomic loss of 8p in MCL.
(A) Summary of chromosomal imbalances detected by CGH in
patients with leukemic MCL. Cases 1 to 19 are as presented in Table 1.
Red lines on the left of the ideogram indicate loss of chromosomal
material, whereas the green lines to the right indicate gain of
chromosomal material. Green squares represent high-level DNA
amplification. (B) Schematic representation of chromosome 8 genomic
abnormalities in patients with MCL and in cell lines with
t(11;14)(q13;q32).
|
|
We subsequently expanded our study to 8 cell lines carrying
t(11;14)(q13;q32). Deletion of 8p21-p23 was identified in 6 of them,
including a genomic gain of 8q24 with MYC amplification in 3 (Figure 1B). In all of them the loss of 8p was caused by an unbalanced
translocation involving 8p and varied partner chromosomes, or by a
derivative isochromosome 8q. These results indicate that the genomic
loss of 8p is a frequent event in MCL cell lines and that concomitant
MYC amplification is seen in most cases. Overexpression and
mutation of MYC has been identified in a subset of lymphomas including Burkitt lymphoma, where it plays a crucial pathogenic role.3,22 However, the clinical and biologic significance of MYC amplification in MCL is not well
known.9,22 Based on our results, we suggest that
MYC amplification in MCL may be especially frequent in cases
with a deletion of 8p. We may therefore hypothesize that an
inactivated TSG at 8p cooperates with MYC in the
pathogenesis of aggressive MCL.
In summary, our results show that genomic loss of 8p is a
characteristic marker of leukemic MCL, suggesting the presence of a
novel TSG locus related to blood dissemination of MCL. The deletion of
8p is frequently accompanied by MYC amplification and
associated with an aggressive behavior of leukemic MCL.
| |
Acknowledgments |
We thank Dr A. Ferrandez (H. Clinico); Drs I. Navarro, R. Ferrer, J. Martinez (H. Gandia); M. Garcia, A. Carral (H. Sagunto); J. Marco, R. Garcia (H. Castellon); M. Montagut, M. D. Mirabet (H. Vinaroz); F. Ortuño (H. Murcia); and all the hematologists and
pathologists from the "Club Citológico de la Comunidad
Valenciana y Murcia" for providing samples and data from the
patients; Dr Mariano Rocci (Bari, Italy) for ATM and BCL2 probes; and
E. Cervello, M. Ordoñez, R. Marques, F. Domingo, and M. Botia,
for excellent technical assistance.
| |
Footnotes |
Submitted February 28, 2001; accepted July 17, 2001.
Supported by grants from the Fondo de Investigación Sanitaria
(FIS) FIS-98/0491 and FIS-01/0015, by the Deutsche Krebshilfe grants 10-1556-Schl4 and 10-1641-De1, and by the IZKF Kiel.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Jose A. Martínez-Climent, Department of
Hematology and Medical Oncology, Hospital Clínico, University
of Valencia. Avda Blasco Ibañez, 17, 46010 Valencia, Spain;
e-mail: martinez_jos{at}gva.es.
| |
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Top
Abstract
Introduction