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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3262-3264
Molecular Characterization of 11q Deletions Points to a Pathogenic
Role of the ATM Gene in Mantle Cell Lymphoma
By
Stephan Stilgenbauer,
Dirk Winkler,
German Ott,
Claudia Schaffner,
Elke Leupolt,
Martin Bentz,
Peter Möller,
Hans K. Müller-Hermelink,
Michael R. James,
Peter Lichter, and
Hartmut Döhner
From the Department of Internal Medicine III, University of Ulm, Ulm,
Germany; the Department of Pathology, University of Würzburg,
Würzburg, Germany; Deutsches Krebsforschungszentrum, Heidelberg,
Germany; the Department of Pathology, University of Ulm, Ulm, Germany;
and Wellcome Trust Centre for Human Genetics, Oxford, UK.
 |
ABSTRACT |
Deletions involving the long arm of chromosome 11 (11q) have been
recently found as recurrent chromosome aberrations in mantle cell
lymphoma (MCL). In the current study, the incidence and molecular extent of 11q deletions were analyzed in a series of 81 MCL by fluorescence in situ hybridization with probes from a contiguous set of
yeast artificial chromosomes (YACs). Loss of chromosome 11 material was
observed in 37 of 81 cases (46%). The minimally deleted segment
comprised YAC 801e11 containing the ATM gene. To further narrow
the minimal region of loss, P1-derived artificial chromosomes mapping
to the critical region were isolated and used as probes in cases
without aberrations detectable with YACs. This allowed the
identification of an ATM deletion that was beyond the
resolution of YAC probes. The identification of a minimally deleted
segment affecting ATM suggests a pathogenic role of ATM as a tumor suppressor gene in MCL.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
MANTLE CELL LYMPHOMA (MCL) is a specific
subtype of non-Hodgkin's lymphoma (NHL) characterized by distinct
clinical, morphological, and genetic features.1 The
cytogenetic hallmark of MCL is the translocation
t(11;14)(q13;q32).2,3 This aberration leads to a
rearrangement of the BCL1 (11q13) and IgH (14q32) loci resulting in the deregulation of the cyclin D1 gene
(CCND1).4-6 The overexpression of CCND1 at
the mRNA and protein levels is highly characteristic of
MCL.6-8 Because the cyclin D1 protein plays a crucial role
in the regulation of G1-S phase transition of the cell cycle, the
CCND1 deregulation by the t(11;14)(q13;q32) is considered
significant for MCL pathogenesis. However, transgenic mice
overexpressing cyclin D1 do not spontaneously develop lymphoma, and
other oncogenic factors such as c-MYC are necessary for tumor formation.9,10 Therefore, additional genetic events appear to be required for the malignant transformation of MCL cells.
By chromosome banding analyses, aberrations in addition to the
t(11;14)(q13;q32) have been found in MCL.11,12 Deletions involving bands 11q22-q23 have been recently observed as recurrent aberrations in MCL13 (and Bentz et al,
submitted), and are also frequent in other B-cell
lymphoproliferative disorders.14 The current study was
aimed at the identification of the minimally deleted segment in 11q
likely harboring a tumor suppressor gene potentially involved in the
pathogenesis of MCL.
| |
MATERIALS AND METHODS |
Tumor samples were prepared from 81 patients with MCL and molecular
cytogenetic analysis was performed as previously
described.14 The specimens of the 37 MCL with 11q deletions
were derived from lymph node (n = 20), peripheral blood (n = 13),
spleen (n = 1), tonsil (n = 1), stomach (n = 1), or conjunctiva
(n = 1). Diagnoses were based on morphologic and immunophenotypic
analyses.1 Among the 37 MCL with 11q deletions, the
t(11;14)(q13;q32) corresponding to a CCND1/IgH rearrangement
was present in all 35 cases tested by our interphase fluorescence in
situ hybridization (FISH) assay.15 Molecular cytogenetic
analysis was performed by dual-color FISH with a physically mapped
probe set of yeast artificial chromosome (YAC) clones (obtained from
the CEPH library, Généthon, Fondation Jean Dausset, Paris,
France) spanning bands 11q14 to 11q24 as previously described (for YAC
numbers, STS markers, and genes contained, see Fig
1).14,16 P1-derived artificial
chromosome (PAC) probes specific for ATM (PAC ATM-1,
LLNLP704G18220Q19; PAC ATM-2, LLNLP704O01298Q19) and for YAC 755b11
(PAC 755b11, LLNLP704H1725Q13) were identified from a human PAC library
(RPCI segments 1, 3-5) obtained from the Resource Center/Reference
Library of the German Human Genome Project (Berlin, Germany) by
hybridization with ATM cDNA clone pCEV7-9 and Alu-polymerase
chain reaction (PCR) products derived from the YAC, respectively. The
ATM exon content of the PACs was determined by PCR
analyses.17
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| Fig 1.
Mapping of deletions involving chromosome bands 11q14 to
11q24 in 37 MCL by FISH. Chromosome 11 ideogram, band designation, CEPH
YAC address, DNA locus, and genes contained in the probe set are given.
YACs 950c12 through 785e12 form a contig and therefore allowed a
precise deletion mapping. del, deletion (1 FISH signal); di, disomy (2 FISH signals); 3, partial trisomy in MCL no. 1 (3 FISH signals). The
extent of the deletion in each case is indicated by shading. The half
shading of YAC 801e11 in MCL no. 33 indicates partial deletion of this
probe. Three MCL (nos. 1, 3, 4) were included in a previous
study.14 The minimal deletion region lost in all MCL
analyzed is the centromeric part of YAC 801e11 to which the ATM
gene maps. The centromeric border of the minimal deletion is defined by
MCL nos. 8 and 21. The telomeric border is defined by MCL no. 33 exhibiting loss of PAC ATM-1 and -2 and retention of 2 signals for YAC
801e11.
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| |
RESULTS AND DISCUSSION |
Screening for 11q deletions was initially performed by interphase FISH
with YAC 755b11 and YAC 801e11 mapping to previously identified
deletion regions in lymphoid neoplasms.14,17,18 Deletions
involving at least one of these probes were observed in 36 of the 81 MCL studied (46%). No biallelic deletion was found. The percentage of
cells carrying a deletion ranged from 13% to 98.5% (median, 84%).
The 46% incidence of 11q loss in MCL is remarkably higher than assumed
from smaller series,13 and exceeds the frequency of 11q
deletions in B-CLL.15 The high incidence of 11q22-q23 deletion, together with the frequent observation of 13q14 deletion in
MCL and B-CLL,19 suggests common genetic mechanisms in the pathogenesis of the two diseases despite their different clinical behavior.
The extent of the 11q deletions was determined by FISH with a probe set
consisting of a YAC contig spanning bands 11q14 to 11q24 (Fig 1). Among
the 36 MCL with 11q deletions detected, a minimal deletion region
affecting YAC 801e11 was established. The genomic segment corresponding
to this YAC probe was lost in all MCL cases with 11q deletions studied
and in one of the MCL was the sole fragment lost (no. 8 in Fig 1). YAC
801e11 is 1.2 Mb in size and contains the genomic region of the
ATM gene.
To further narrow the minimal deletion segment and to test whether
ATM or an adjacent locus was affected by the 11q deletions in
MCL, we isolated PACs containing ATM coding sequence (PAC ATM-1 and -2) and a PAC from the YAC 755b11 region (PAC 755b11). Exons 4 to
49 and exons 25 to 65 of the ATM gene were contained in PAC ATM-1 and -2, respectively, as detected by PCR analysis. Forty MCL
cases showing no aberration on initial FISH screening with YACs 801e11
and 755b11 were subjected to analysis with these PAC probes. One MCL
(no. 33, Fig 1) was found to carry a deletion of the genomic region
corresponding to PAC ATM-1 and -2. Subsequent analysis with YAC probes
showed that this MCL carried a deletion extending in centromeric
direction (see Fig 1). Because PAC ATM-1 and -2 are located in the
centromeric end of YAC 801e11, this further narrowed the minimal
deletion region lost in all MCL with 11q deletions analyzed to the
centromeric portion of YAC 801e11 where the ATM gene resides
(Fig 1). Also affected by the minimal deletion is NPAT, which
is located centromeric of ATM and shares the same promoter
region. However, there are no data suggesting a tumor suppressor
function for NPAT and it has not been linked to hematological
neoplasms. Interestingly, our data are at variance to a concurrent
report by Monni et al,20 who analyzed 20 MCL with 11q
deletions by FISH. In this study, one MCL with an isolated deletion of
the genomic region of YAC 755b11 was identified, which is located 2 to
3 Mb telomeric of ATM. In all other cases, larger deletions
also affecting ATM were found.
Disruption of both ATM alleles in line with the two-hit model
of tumor suppressor gene inactivation was previously demonstrated in
T-PLL.17,18 In addition, recent studies showed loss of
ATM protein expression and mutational disruption of ATM
in B-cell chronic lymphocytic leukemia, suggesting a
pathogenic role also in B-cell malignancies.21-24 The
identification of an 11q22-q23 minimal deletion region in MCL tumor
cells specifically affecting ATM points to a role of
ATM as a tumor suppressor gene in MCL. This is supported by the
fact that in a series of B-cell neoplasms recently analyzed there were
two MCL cases showing ATM mutations.24 In one of
these cases mutations were found in both ATM alleles in the
absence of a genomic deletion.
Although the function of the ATM gene product is not fully
established, studies of ataxia-telangiectasia cell lines and
ATM-deficient mice have shown that ATM is a key
regulator in response to DNA strand breaks induced by mutagenic agents
or physiological processes such as VDJ recombination.25 In
this context, it is interesting to note that the hallmark of MCL is the
rearrangement of the IgH locus with the proto-oncogene
CCND1 as a result of illegitimate VDJ recombination. Based on
the current results, this aberrant VDJ recombination in MCL and the
subsequent acquisition of additional genetic changes leading to complex
karyotypes could result from a faulty surveillance of the genomic
integrity by loss of the ATM gene product.
| |
ACKNOWLEDGMENT |
The excellent technical assistance of Kathrin Wildenberger and Traudel
Weilguni is gratefully acknowledged. Yosef Shiloh generously provided
the pCEV7-9 ATM cDNA clone. The PACs were isolated from libraries created in the laboratory of P.J. de Jong at Roswell Park
Cancer Institute (Buffalo, NY) and generously provided by the Resource
Center/Primary Database of the German Human Genome Project (Berlin, Germany).
| |
FOOTNOTES |
Submitted March 30, 1999; accepted July 1, 1999.
Supported by grants from the Deutsche Krebshilfe (10-1289-St 1), the
Wilhelm Sander-Stiftung (97.003.1), and the Tumorzentrum Heidelberg/Mannheim (I/I.1).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Hartmut Döhner, MD,
Department of Internal Medicine III, University of Ulm, Robert Koch Str
8, 89081 Ulm, Germany.
| |
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ABSTRACT
INTRODUCTION