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NEOPLASIA
From the Departments of Anatomic Pathology and
Hematology, Hospital Clinic, Institut d'Investigacions
Biomèdiques August Pi i Sunyer, University of Barcelona, Spain;
and Centro de Investigación del Cáncer, CSIC-University of
Salamanca, Spain.
The ataxia-telangiectasia mutated (ATM) gene
codifies for a protein critically involved in the cellular response to
DNA damage. ATM alterations have been observed in some sporadic
lymphoproliferative disorders. The recurrent 11q22-23 deletions found
in mantle cell lymphoma (MCL) suggest that ATM could be inactivated in
these lymphomas. In this study, ATM gene alterations and
protein expression were examined in 20 and 17 MCL tumor specimens,
respectively. Previously, these patients had been examined for
p53 and p14ARF gene status and
analyzed by comparative genomic hybridization. Nine patients had
11q22-23 losses. Eight ATM gene mutations were detected in
7 patients. These alterations were 3 missense mutations in the
phosphatidylinositol-3 kinase (PI-3K) domain and 5 truncating mutations, including 3 frameshifts, a nonsense mutation, and a substitution of the initial methionine. All truncating mutations were
associated with lack of protein expression. Somatic origin was
demonstrated in 3 mutations, whereas one mutation was carried heterozygously in the patient germ line. Chromosomal imbalances were
significantly higher in typical MCL with ATM inactivation (7.8 ± 1.3) than in tumors with the wild-type gene
(3 ± 1.1) (P = .001). Moreover, tumors with bi-allelic
ATM alteration were associated with 3q gains (P = .015)
and frequent extranodal involvement (P = .049).
ATM gene alterations were not related to the histologic variant of the tumors, p53/p14ARF gene status,
survival, or other clinicopathologic features of the patients. These
findings indicate that ATM gene mutations in MCL are mainly
truncating or missense mutations involving the PI-3K domain, and that
may play a role in the pathogenesis of a subset of these tumors with
increased numbers of chromosomal imbalances.
(Blood. 2002;99:238-244) Mantle cell lymphoma (MCL) is a lymphoproliferative
disorder characterized by the t(11;14) (q13;q32) translocation, which leads to the rearrangement and overexpression of the cyclin
D1 gene.1,2 However, the tumorigenic and
transforming potential of cyclin D1 in experimental models is
relatively limited, and it requires the cooperation of other oncogenic
factors such as c-myc.3 Additional alterations
in the tumor suppressor genes p16INK4a and
p53 have been described in aggressive variants of MCL,
suggesting that these genes may cooperate with cyclin D1
overexpression in the progression of these lymphomas.4-7
Classical cytogenetic and comparative genomic hybridization (CGH)
studies have shown a high number of recurrent chromosomal alterations
in MCL, indicating that other genes may be involved in the pathogenesis
of these tumors.8-10 One of the most frequent secondary
chromosomal aberrations in MCL is the loss of the 11q22-23 region,
where the ataxia-telangiectasia mutated (ATM) gene is
located.11,12
Mutations in the ATM gene are responsible for the
ataxia-telangiectasia (AT) syndrome, a rare autosomal recessive
disorder characterized by progressive cerebellar ataxia, ocular
telangiectasia, immunodeficiency, high sensitivity to ionizing
radiation, and predisposition to lymphoid malignancies.13
AT cells show chromosomal instability, telomere shortening, and defects
in response to ionizing radiation and radiomimetic
drugs.14 Mutations and deletions in the ATM
gene have also been found in a variety of sporadic neoplasias,
including T-prolymphocytic leukemia (T-PLL)15-17 and B-cell
chronic lymphocytic leukemia (B-CLL).18,19 More recently, ATM mutations have been identified in MCL, mainly associated
with 11q22-23 deletions.20 However, the incidence of these
mutations in tumors with no alterations in chromosome 11 and the
possible relation between ATM inactivation and morphologic variants of tumors and the clinicopathologic characteristics of patients are unknown.
ATM gene encodes for a serine-threonine kinase belonging to
the phosphatidylinositol-3 kinase (PI-3K) family. This enzyme plays a
central role in signaling pathways activated by DNA
damage.21-23 Different studies have now identified a
number of ATM targets including c-abl, p53, Chk-2, Nbs-1,
and BRCA-1.21,24-27 Particularly, p53 seems to participate
in the ATM regulation of the G1/S checkpoint activated by DNA damage.
Thus, in response to different DNA damaging agents, ATM phosphorylates
p53, promoting its stabilization and transcriptional activation and
leading to cell cycle arrest, DNA repair, or
apoptosis.26,28 p53 Gene inactivation has been
recognized as a frequent phenomenon in the pathogenesis of aggressive
variants of lymphoproliferative disorders including MCL. However, the
possible relation between p53 and ATM inactivation in the development
and progression of human tumors is not well known.
The aim of this study was to analyze the role of ATM gene
alterations in the pathogenesis of MCL and possible relationships with
genetic, clinical, and pathologic characteristics of the tumors. Our
findings indicate that ATM gene inactivation is a relatively
frequent phenomenon in these lymphomas, mainly occurring by truncating
mutations and nucleotide substitutions in the PI-3K domain. ATM
aberrations are independent of p53 gene status, and they are
associated with a significantly higher number of chromosomal imbalances
in typical variants of MCL.
Tumor selection
RNA extraction and reverse
transcription-polymerase chain reaction
Restriction endonuclease fingerprinting and sequencing analyses The whole ATM coding region was screened for mutations using restriction endonuclease fingerprinting (REF) analysis and direct sequencing in 17 MCL specimens, following previously described protocols.30,31 In each gel, wild-type DNA from reactive tonsils was included to determine the normal restriction patterns of the analyzed fragments. Direct sequencing of positive reverse transcription-PCR products was performed by cycle sequencing dRhodamine or BigDye terminator chemistry (Applied Biosystems). Sequencing reactions were run on a Perkin-Elmer ABI-377 automated sequencer. All mutations were confirmed by sequencing both strands. In 3 additional samples with normal ATM protein expression and 11q CGH profile, only the PI-3K domain was analyzed by direct sequencing.Germline studies To analyze the germline status of the ATM gene, constitutional normal DNA was obtained in 6 specimens. In 3, DNA was extracted from peripheral blood granulocytes separated by density gradient centrifugation. In the remaining samples, constitutional DNA was obtained from normal tissue microdissected from frozen tissue sections. Microdissection was carried out using the laser pressure catapulting technique of the Robot-microbeam system (P.A.L.M. GmbH, Benried, Germany). DNA extraction from microdissected samples was performed as described elsewhere.32 Possible contamination of these normal DNA samples by tumor cells was ruled out by analysis of the immunoglobulin heavy chain gene, bcl-1 rearrangement, or both.33PCR amplifications of the ATM gene were performed using a
hemi-nested strategy with primers flanking the genomic region in which
the mutations were located in the tumor complementary DNA (Table
1). The first PCR amplification
conditions were 35 cycles at 94°C for 1 minute, 55°C to 60°C for
1 minute, and 72°C for 1.5 minutes. The amplification profile of the
second PCR round was the same, with an annealing temperature ranging
from 60°C to 65°C depending on the particular amplification.
Finally, direct sequencing using the same PCR primers was
performed.
Protein extraction and Western blot analysis Nuclear protein extracts were obtained from 17 MCL samples in which additional frozen tissue was available. Cryostat frozen sections were lysed in ice-cold buffer containing 10 mM HEPES (pH 7.9), 10 mM KCl, 1.5 mM MgCl2, 0.1% Nonidet P-40, 0.5 mM dithiothreitol, 2 µg/mL leupeptin, 5 µg/mL aprotinin, and 0.5 mM phenylmethylsulfonyl fluoride for 15 minutes. After centrifugation at 3500 rpm, the precipitated nuclei were lysed in a buffer containing 80 mM Tris-HCl (pH 6.8), 2% sodium dodecyl sulfate, and 10% glycerol. Eighty micrograms nuclear protein was run per lane on a 5% sodium dodecyl sulfate-polyacrylamide gel and electroblotted to a nitrocellulose membrane (Amersham, Buckinghamshire, United Kingdom). Membranes were blocked by overnight incubation in 5% dry milk and 0.1% Tween-20 at 4°C. Blocked membranes were then incubated with the polyclonal antibody anti-ATM Ab3 (Oncogene Research, Boston, MA) overnight at 4°C, washed with phosphate-buffered saline 0.1% Tween-20, and incubated with a sheep anti-rabbit secondary antibody conjugated to horseradish peroxidase (Amersham). Polyclonal antibody antipoly ADP ribose polymerase (PARP) (Oncogene Research) was used as a loading control in all cases. After washing, antibody binding was detected by chemiluminescence detection procedures according to the manufacturer's recommendations (ECL; Amersham). Intensities of the ATM proteins were normalized to the PARP band signal.Statistical analysis Tumors were grouped according to histologic subtype and ATM gene status (wild-type and 1 or 2 affected ATM alleles). The following clinicopathologic variables were recorded and included in the analysis: age, sex, histologic subtype, performance status, stage (Ann Arbor), extranodal involvement (0 or 1 vs 2 or more sites), lactate dehydrogenase serum level, International Prognostic Index, response to therapy (complete or partial vs failure), peripheral blood involvement, length of survival from diagnosis, number of chromosomal imbalances, and different chromosomal aberrations. Comparison between the number of chromosomal imbalances detected by CGH and the status of ATM alleles was performed using the Kruskal-Wallis test. Associations between ATM inactivation and the presence of a particular clinicopathologic parameter were evaluated with the 2-tailed Fisher exact test. Probability of survival was calculated using the method of Kaplan and Meier,34 and different curves were statistically compared by means of the log-rank test.35 Level of significance was set at .05 for all analyses.
Mutational analysis The entire coding region of the ATM gene was initially examined in 17 MCL samples. Nine had been shown by CGH analysis to exhibit 11q losses, including the 11q22-23 region. In this group, 6 ATM gene mutations were identified in 5 tumors (Table 2). Four of these mutations (in samples 1, 7, and 8) predicted premature termination of the protein lacking the PI-3K domain. Two additional alterations (samples 2 and 6) were missense mutations (9023 G A and 8174 AT, respectively)
leading to an amino acid change in conserved residues of the PI-3K
domain. Truncating mutations included an insertion and a small deletion
causing frameshift changes and creating stop codons, a nonsense
mutation, and a substitution of the initial methionine (Table 2). In
sample 1, 29 nucleotides from the intron 28 sequence were inserted at
position 4182 of the mRNA, causing a frameshift in the open-reading
frame predicting a protein truncation 17 amino acids after the
insertion point. This insertion had been previously recognized in
T-PLL.15 The inserted sequence corresponds to a fragment
of the intron 28 flanked by potential acceptor and donor splicing
sites.36 As in the previously described T-PLL sample, no
alterations in the genomic sequence were found. Tumor 8 showed a CT
transition at codon 67 creating a stop codon at R23, exhibiting an
additional downstream 4-bp deletion ( 73-76) that caused the
generation of a second stop codon. The lack of a normal allele in the
REF analysis and sequencing plot and the 11q loss present in this tumor
suggest that both mutations were in the same allele. Normal DNA from
this patient could be obtained from peripheral blood granulocytes. The
67CT transition was present in heterozygosity in the germline. However, the second mutation was only present in the tumor sample, indicating a somatic origin. The third truncating mutation in these
tumors was observed in specimen 7. This MCL showed the nucleotide change 1AT, which resulted in the substitution of the initial methionine codon preventing protein translation. All truncating mutations were associated with a total absence of protein expression on
Western blot analysis (see below).
In the 8 MCL specimens without 11q deletions by CGH, ATM
gene mutations were detected in 2. Sample 12 showed a nucleotide change
(8150 A
Because all ATM gene aberrations in the previous 17 tumors were truncating mutations that led to lack of protein expression or nucleotide substitutions in the PI-3K domain, we expanded the protein analysis and the mutational study of the PI-3K domain in 3 additional tumors with no 11q deletions. Western blot analysis showed normal levels of ATM protein expression in all tumors (see below), suggesting that they did not have truncating mutations (Table 2). In addition, no mutations were identified in the PI-3K domain. Polymorphic variants In the mutational analysis of this series of MCL, various polymorphic changes were also identified (Table 2). The D3003N/Q3031Q polymorphism37 and the change A554T, not previously recognized as an ATM polymorphic variant, were detected in all tumor specimens, normal DNA from the same patients, and 10 additional DNA samples from Spanish blood donors. These findings indicate that the changes may represent the wild-type ATM allele in our geographic area. Because these changes were present in all patients, they are not included in Table 2. The polymorphic variant D1853N was present in this series at a lower prevalence (8%) than that previously recognized in the healthy population (16%).38 The 3161 CG, P1054R nucleotide change found in one MCL specimen had previously been
described as a polymorphic variant.39 Two nucleotide
changes that did not cause amino acidic substitutions (1428 AG,
Q476Q and 7458 GA, R2486R) were identified in 7 tumor specimens. Two additional nucleotide substitutions, N750K and C532Y, were identified in 13 (77%) and 1 (6%) tumors, respectively. Both changes were also
identified in the respective normal DNA of the patients and in healthy
blood donors with allele frequencies similar to those of tumor patients
(0.9 and 0.05, respectively). Interestingly, the N750K variant had been
recognized as a possible ATM mutation in one MCL
tumor.20 However, no normal DNA from the same patient could be examined. The findings in our study indicate that this change
is a polymorphic variant frequently found in the healthy population.
Protein expression analysis ATM protein expression was examined in 17 tumors. Five showed a complete absence of ATM protein (Figure 2). Four of these lymphomas (specimens 1, 7, 8, 13) had truncating mutations and also showed concordant absence of the paired allele in the CGH analysis (specimens 1, 7, 8) and sequencing studies (specimens 1, 7, 8, 13). No gene mutations were detected in an additional tumor (specimen 3) with no protein expression in spite of sequencing the full coding region. Three tumors showed relatively low levels of protein expression. Two of these had an 11q deletion by CGH (specimens 2 and 9). The third tumor (specimen 12) had a missense mutation in the PI-3K domain, but the CGH analysis did not show an 11q loss. Low levels of ATM protein in this tumor suggested the presence of an additional truncating mutation or microdeletion in the paired allele that was not detected in the mutational or CGH studies. Relative normal levels of protein expression were observed in the remaining specimens (Table 2).
ATM inactivation and clinicopathologic features ATM gene and ATM protein alterations were detected at a relatively similar incidence in typical (4 of 12, 33%) and blastoid (4 of 8, 50%) MCL variants. In addition, p53 and p14ARF gene alterations had been previously analyzed in this series.29 Four showed p53 gene alterations, including 2 mutations and 2 homozygous deletions. One showed a homozygous deletion of the INK4a/ARF locus. Tumors with homozygous deletions of the p53 gene and the INK4/ARF locus also had mutations of the ATM gene. However, no ATM alterations were detected in the 2 additional tumors with p53 mutations (Table 2).To determine the possible relation between ATM gene
alterations and number of chromosomal imbalances, tumors were grouped according to the status of the ATM gene. Thus, MCL with no
gene mutations or allelic losses and normal protein expression were considered tumors with wild-type ATM (samples 10, 11, 14-20). Tumors
with biallelic alterations of the ATM gene included those with gene mutations associated with losses of the paired allele (samples 1, 2, 6-8, 12, 13). Sample 3, showing complete absence of
protein expression on Western blot analysis, was also included in this
group. Finally, tumors in which no gene mutations were detected on REF
analysis but in which the CGH study showed 11q losses were considered
to have monoallelic alterations (samples 4, 5, 9). Typical MCL with the
wild-type ATM gene had significantly lower numbers of
chromosomal imbalances (mean, 3; SD, 1.1) than tumors with inactivation
of both alleles (mean, 7.8; SD, 1.3) (P = .001). The 2 typical MCL tumors with monoallelic ATM alterations had an intermediate
number of CGH alterations (mean, 6.5) (Figure 3). However, all blastoid MCL had a high
number of chromosomal imbalances with no differences between samples
with wild-type ATM (mean, 10.4; SD, 8.5), monoallelic (n = 9), or
biallelic ATM alterations (mean, 9.5; SD, 1.7) (Figure 3).
Additionally, biallelic ATM alterations were associated with the presence of the +3q chromosomal abnormality (biallelic altered, 87% vs wild-type 22%; P = .015). Moreover, a statistical trend was observed with the +12q abnormality (biallelic altered, 60% vs wild-type, 0%; P = .082). Biallelic ATM inactivation was also associated with the presence of extranodal involvement (2 or more sites affected) (altered, 62% vs wild-type, 11%; P = .049). The same significant variables were obtained when the 3 tumors with monoallelic ATM alteration were included in the group of tumors with biallelic ATM alteration. Median survival time in this series was 48 months (95% CI, 40-56 months). Median survival time when tumors had typical histology was 70 months, whereas it was 24 months for the blastoid variants. No statistical differences in survival were observed when grouped according to the ATM gene status.
In this study, we have analyzed ATM gene alterations and ATM protein expression in a series of 12 typical and 8 blastoid variants of MCL. All these tumors had been previously characterized for the status of the p53 and ARF genes.29 Chromosomal imbalances had been examined by CGH.9 ATM alterations were detected in 8 (40%) tumors, including 6 of 9 (67%) lymphomas with 11q losses and 2 of 11 (18%) tumors in which the CGH analysis showed a normal chromosome 11 profile. However, protein analysis and sequencing plots suggested that the paired allele in these 2 tumors was also inactivated. ATM alterations were slightly more frequent in blastoid (50%) than in typical (33%) variants, but the differences were not statistically significant. These findings indicate that ATM inactivation is a frequent phenomenon in MCL. The number of these alterations in typical variants suggests that they may be a relatively initial event in the development of these tumors. ATM gene and ATM protein alterations have been previously recognized in other lymphoproliferative disorders, including 46% to 67% T-PLL and 19% to 34% B-CLL.15-19,40 More recently, Schaffner et al20 have identified ATM mutations in 7 (100%) MCL with 11q22-23 deletions and in 2 of 5 (40%) MCL with no chromosome 11q losses. Although the number of ATM alterations in our study was relatively lower, these observations together confirm the role of ATM inactivation in the pathogenesis of MCL. Most ATM mutations in T-PLL are missense mutations clustering in the PI-3K domain or are truncating mutations leading to the absence or early termination of the protein.15-17 In contrast, ATM mutations in B-CLL are mainly missense changes outside the kinase domain.18,19,40 In our study, 3 missense mutations were detected in conserved positions of the PI-3K domain, and 4 additional changes led to absence or early truncation of the protein. One additional tumor had a complete absence of protein expression, but no structural gene alterations were found. In the previous study on MCL, the mutations detected were mainly truncating changes and one missense substitution in the PI-3K domain. Two additional missense changes (N750K and E2423G) were located in other regions of the gene. However, the possible polymorphic significance of these nucleotide substitutions could not be assessed.20 In our study, we found that one of these changes (N750K) was present in 77% of the tumors, in normal DNA of the patients, and in a healthy population with a high allele frequency (0.9), indicating that this nucleotide substitution is a relatively common polymorphism. These observations confirmed that ATM inactivation in MCL follows a pattern similar to that for T-PLL, with truncating mutations and changes clustering in the kinase domain. Our observations differ from the findings in B-CLL, in which most mutations are missense substitutions distributed in different areas of the gene. All mutations detected in our study predicted a potential inactivation of the protein function. Two of the 3 missense mutations in the PI-3K domain occurred at R3008 and D2725, 2 conserved amino acid positions that have mutated in B-CLL, T-PLL, and one MCL, suggesting that they may be crucial spots in protein inactivation.17,20,40 The third mutation, K2717M, has not previously been recognized but also involves a highly conserved amino acid in different members of the PI-3K family.17 The remaining ATM mutations found in our series were frameshift or nonsense mutations leading to absent proteins or truncating proteins. Two of these mutations have been initially recognized in patients with T-PLL (sample 1) and AT (sample 7).15,41 In this latter, however, the nucleotide substitution was identified in the first position whereas in the former it was in the second nucleotide.41 Sample 8 showed 2 simultaneous truncating mutations, apparently in the same allele. Interestingly, multiple structural lesions in one allele of the ATM gene have also been observed in several patients with T-PLL.17 The significance of these multiple changes in the ATM gene is unclear. In this MCL series, ATM protein expression was concordant with the status of the gene and the presence of allelic losses in virtually all samples. Thus, tumors with truncating mutations and 11q loss by CGH showed a complete absence of protein expression, suggesting that these mutations prevented translation or generated unstable products. Samples with allelic losses associated with missense mutations or wild-type genes in the paired allele expressed low levels of protein. Normal protein signal was observed in samples with no apparent alterations of the gene. Only 2 samples (samples 3 and 12) showed discordance between protein expression and gene status. The ATM protein in these 2 samples was absent and low, respectively. However, sample 3 showed an 11q loss, but no mutations were detected in the remaining allele. Similarly, sample 12 with no 11q loss showed a missense mutation only in one allele. REF analysis is considered of high sensitivity for the detection of gene mutations,31 but it is possible that occasional truncating alterations or microdeletions were unidentified in these tumors. Germline ATM mutations have been detected in patients with B-CLL,18,37 suggesting a possible role of ATM in the genetic predisposition of this disorder. In the current series, 2 tumor mutations were not present in the normal DNA of the patients (samples 12 and 13), indicating their somatic origin. Interestingly, in sample 8, 1 of the 2 simultaneous mutations (R23stop) was carried in heterozygosity in the germline of the patient. However, the tumor sample of this patient had lost the wild-type allele and had acquired a second 4-bp deletion downstream of the constitutional mutation. Germline heterozygous ATM gene mutations have been estimated to be present in approximately 0.5% to 5% of the general population.42,43 Whether these mutations may cause significant genetic predisposition to the development of malignancies is still debatable. One of the targets of the ATM protein function is p53.26,28,44 Inactivation of p53 is a frequent phenomenon in aggressive MCL and other lymphoproliferative disorders. However, the possible relation between the genetic alterations of these 2 genes in human tumors is unknown. In T-PLL, in which ATM inactivation is relatively common, no p53 mutations have been detected, suggesting that ATM and p53 could have an alternative pathogenetic role.17 However, in the current study, p53 mutations were found either in tumors with ATM inactivation or in tumors with wild-type ATM, suggesting that these 2 alterations may act independently in the development of MCL. The ATM gene plays a central role in the cellular response to DNA damage. Human and murine cells deficient in the ATM gene present an increasing number of chromosomal abnormalities and genetic instability.14 A possible association between ATM gene alterations and chromosomal aberrations in human tumors has not been previously explored. In this study, we have observed a significantly higher number of chromosomal imbalances in typical MCL with ATM gene alterations than in tumors with wild-type ATM, suggesting that ATM inactivation may favor increasing chromosomal instability in these lymphomas. The fact that blastoid variants have a high number of chromosomal imbalances independent of ATM gene status suggests that other genes may be involved in the pathogenesis of these variants and in their chromosomal instability. In conclusion, our findings indicate that the ATM gene is frequently inactivated in MCL. The relatively similar number of alterations in typical and blastoid variants suggests that ATM may be involved in early steps of tumor development. ATM gene mutations are mainly truncating or, alternatively, missense mutations in conserved residues of the PI-3K domain, and they seem independent of p53 alterations. The significant association between ATM inactivation and higher number of chromosomal imbalances in typical MCL suggests a possible role of these aberrations in increasing chromosomal instability in these tumors.
We thank Iracema Nayach and Olga Luna for excellent technical assistance. Sequencing analysis was performed using the Serveis Científico-Tècnics of the University of Barcelona.
Submitted April 3, 2001; accepted August 17, 2001.
Supported by the Comision Interministerial de Ciencia y Tecnologia (CICYT) SAF 99/20, European Commission contract QLRT-1999-30687, FEDER 1FD97-1678, and CIRIT, Generalitat de Catalunya 2000SGR118.
E.C. and L.H. contributed equally to this study.
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: Elias Campo, Laboratory of Pathology, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain; e-mail: campo{at}medicina.ub.es.
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E. Gine, M. Crespo, A. Muntanola, E. Calpe, M. J. Baptista, N. Villamor, E. Montserrat, and F. Bosch Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment Haematologica, January 1, 2008; 93(1): 75 - 82. [Abstract] [Full Text] [PDF]
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D. Kienle, T. Katzenberger, G. Ott, D. Saupe, A. Benner, H. Kohlhammer, T. F.E. Barth, S. Holler, J. Kalla, A. Rosenwald, et al. Quantitative Gene Expression Deregulation in Mantle-Cell Lymphoma: Correlation With Clinical and Biologic Factors J. Clin. Oncol., July 1, 2007; 25(19): 2770 - 2777. [Abstract] [Full Text] [PDF]
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T. Ripperger, N. von Neuhoff, K. Kamphues, M. Emura, U. Lehmann, M. Tauscher, M. Schraders, P. Groenen, B. Skawran, C. Rudolph, et al. Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle cell lymphomas Haematologica, April 1, 2007; 92(4): 460 - 468. [Abstract] [Full Text] [PDF]
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I. Salaverria, A. Zettl, S. Bea, V. Moreno, J. Valls, E. Hartmann, G. Ott, G. Wright, A. Lopez-Guillermo, W. C. Chan, et al. Specific Secondary Genetic Alterations in Mantle Cell Lymphoma Provide Prognostic Information Independent of the Gene Expression-Based Proliferation Signature J. Clin. Oncol., April 1, 2007; 25(10): 1216 - 1222. [Abstract] [Full Text] [PDF]
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V. Fernandez, E. Hartmann, G. Ott, E. Campo, and A. Rosenwald Pathogenesis of Mantle-Cell Lymphoma: All Oncogenic Roads Lead to Dysregulation of Cell Cycle and DNA Damage Response Pathways J. Clin. Oncol., September 10, 2005; 23(26): 6364 - 6369. [Abstract] [Full Text] [PDF]
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D. Kienle, A. Krober, T. Katzenberger, G. Ott, E. Leupolt, T. F. E. Barth, P. Moller, A. Benner, A. Habermann, H. K. Muller-Hermelink, et al. VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome Blood, October 15, 2003; 102(8): 3003 - 3009. [Abstract] [Full Text] [PDF]
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J. Starczynski, W. Simmons, J. R. Flavell, P. J. Byrd, G. S. Stewart, H. S. Kullar, A. Groom, J. Crocker, P. A.H. Moss, G. M. Reynolds, et al. Variations in ATM Protein Expression During Normal Lymphoid Differentiation and Among B-Cell-Derived Neoplasias Am. J. Pathol., August 1, 2003; 163(2): 423 - 432. [Abstract] [Full Text] [PDF]
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N. Y. Fang, T. C. Greiner, D. D. Weisenburger, W. C. Chan, J. M. Vose, L. M. Smith, J. O. Armitage, R. A. Mayer, B. L. Pike, F. S. Collins, et al. Oligonucleotide microarrays demonstrate the highest frequency of ATM mutations in the mantle cell subtype of lymphoma PNAS, April 29, 2003; 100(9): 5372 - 5377. [Abstract] [Full Text] [PDF]
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M. Sanchez-Beato, A. Sanchez-Aguilera, and M. A. Piris Cell cycle deregulation in B-cell lymphomas Blood, February 15, 2003; 101(4): 1220 - 1235. [Abstract] [Full Text] [PDF]
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F. Tort, S. Hernandez, S. Bea, A. Martinez, M. Esteller, J. G. Herman, X. Puig, E. Camacho, M. Sanchez, I. Nayach, et al. CHK2-decreased protein expression and infrequent genetic alterations mainly occur in aggressive types of non-Hodgkin lymphomas Blood, December 15, 2002; 100(13): 4602 - 4608. [Abstract] [Full Text] [PDF]
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K. Gronbak, J. Worm, E. Ralfkiaer, V. Ahrenkiel, P. Hokland, and P. Guldberg ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma Blood, July 30, 2002; 100(4): 1430 - 1437. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
