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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 748-753
Somatic ATM Mutations Indicate a Pathogenic Role of ATM in
B-Cell Chronic Lymphocytic Leukemia
By
Claudia Schaffner,
Stephan Stilgenbauer,
Gudrun A. Rappold,
Hartmut Döhner, and
Peter Lichter
From Abteilung "Organisation komplexer Genome", Deutsches
Krebsforschungszentrum, Heidelberg; Medizinische Klinik und Poliklinik
V, University of Heidelberg, Heidelberg; and the Institut für
Humangenetik, University of Heidelberg, Heidelberg, Germany.
 |
ABSTRACT |
Deletion in chromosome bands 11q22-q23 is one of the most common
chromosome aberrations in B-cell chronic lymphocytic leukemia (B-CLL).
It is associated with extensive lymph node involvement and poor
survival. The minimal consensus deletion comprises a segment, which
contains the ATM gene presenting an interesting candidate gene, as
mutations in ATM predispose A-T patients to lymphoid
malignancies. To investigate a potential pathogenic role of ATM in
B-cell tumorigenesis, we performed mutation analysis of ATM in
29 malignant lymphomas of B-cell origin (B-CLL = 27; mantle cell
lymphoma, [MCL] = 2). Twenty-three of these carried an 11q22-q23
deletion. In five B-CLLs and one MCL with deletion of one ATM
allele, a point mutation in the remaining allele was detected, which
resulted in aberrant transcript splicing, alteration, or truncation of
the protein. In addition, mutation analysis identified point mutations
in three cases without 11q deletion: two B-CLLs with one altered allele
and one MCL with both alleles mutated. In four cases analyzed, the
ATM alterations were not present in the germ line indicating a
somatic origin of the mutations. Our study demonstrates somatic
disruption of both alleles of the ATM gene by deletion or point
mutation and thus its pathogenic role in sporadic B-cell lineage tumors.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
MUTATIONS IN THE ATM (ataxia
telangiectasia mutated) gene are responsible for the autosomal
recessive disorder ataxia telangiectasia (A-T). A-T is characterized by
neurologic degeneration, immunodeficiency, infertility, radiation
sensitivity, and a marked predisposition to cancer (for review, see
Sedgewick and Boder,1 Lavin and Shiloh,2 and
Jeggo et al3). The cellular phenotype of A-T includes
hypersensitivity to ionizing radiation, genome instability, and
dysregulation of the cell cycle checkpoints.2,3 The ATM
gene is localized in the chromosomal region 11q22.3-q23.1 and consists
of 66 exons spanning 146 kb of genomic DNA. The gene encodes a
370-kD nuclear phosphoprotein sharing homology with phosphatidylinositol 3-kinase (PI-3-K). It is known that
PI-3-K-related proteins function in DNA repair, in DNA recombination,
and in cell cycle control.4-10
One of the most intriguing features of A-T is the increased
predisposition to develop malignancies. The predominant cancers among
these are neoplasms of the lymphoid system including both B- and T-cell
tumors11 with a risk for leukemia approximately 70 times
higher than in the normal population.12 Individuals with
heterozygous ATM mutations have also been suggested to be at
elevated risk for cancer, particularly for carcinoma of the breast.13 Several studies of breast cancer patients,
however, did not find ATM mutations in a frequency higher than
expected by chance (eg, Vorechovsky et al,14 FitzGerald et
al,15 Bay et al,16 and Chen et
al17). Thus, the role of ATM in breast tumors remains
unresolved. Recently, biallelic mutations of the ATM gene have been
identified in T-prolymphocytic leukemia (T-PLL) of patients
without A-T history indicating a tumor-suppressor function of ATM in
sporadic T-PLL.18-21 Although loss of heterozygosity in the
11q22-q23 region has been frequently observed in various types of
tumors22 (and references therein), to date T-PLL is the
only sporadic tumor for which recurrent somatic inactivation of both
alleles of the ATM gene has been demonstrated.
In B-cell chronic lymphocytic leukemia (B-CLL), we identified deletion
of the chromosomal region 11q22-q23 as a recurrent aberration by using
fluorescence in situ hybridization (FISH) in a large series of more
than 200 B-CLLs.23,24 Loss of the region was shown to be a
prognostic marker predicting poor survival.24 The commonly
deleted region was defined as a 2 to 3 megabasepairs (Mbp)
segment, which contains the ATM, DDX10, RDX
(radixin), and FDX1 (ferredoxin 1) genes.23,24 The
frequent monoallelic deletion of the gene in sporadic B-CLL and the
association between ATM inactivation and the development of T-
and B-cell leukemia in A-T patients had led us to analyze the ATM gene
in malignant B-cell lymphoma.
| |
MATERIALS AND METHODS |
Patient and control material.
The study comprised 29 patients with malignant lymphoma of B-cell type
and 50 unrelated healthy probands of central European origin. Samples
were collected after informed consent. Based on morphology and
immunophenotype, the tumors were classified as B-CLL (n = 27) and
mantle cell lymphoma (MCL, n = 2). Dual-color interphase FISH detected
deletions of chromosome bands 11q22-q23 in 22 of the B-CLL cases and
one of the MCL cases (MCL-A) and translocations affecting 11q23 in two
B-CLLs (B-CLL-F and -H). Many of these cases were contained in the
study by Stilgenbauer et al.23 Both MCLs were shown to have
a t(11;14)(q13;q32). None of the patients had clinical evidence for
A-T. From six B-CLL patients and one MCL patient, skin biopsies were
available serving as specimen for the analysis of the ATM
germline status.
Mutation analysis of the ATM gene.
Total RNA and genomic DNA from mononuclear cell preparations of
malignant B-cell lymphomas and control persons were extracted with the
Trizol reagent (Gibco BRL, Eggenstein, Germany). Genomic DNA from skin
biopsy cells was isolated with the QIAamp kit (Qiagen, Hilden, Germany)
and from normal healthy controls by the standard phenol-chloroform method.
The following oligonucleotides were used for polymerase chain reaction
(PCR) and sequence analysis:
1A, 1B, 2A, 2B, 4A, 4A2, 4B, 5A, 5B, 6A, and 6B are listed in
Stilgenbauer et al.18 Additionally used primers were 1A1
(exon 38) 5'-TGGATAAAGACACTGACT-3'; 1A2 (exon 39/40)
5'-GGATTCAGAGTCAGAGCAC-3'; 1B1 (exon 41)
5'-CAGCACAAGACTGAGCTACC-3'; 3A (exon 42/43)
5'-CTGGAATAAGTTTACAGGATCTTC-3'; 3B (exon 51)
5'-GATGATTTCATGTAGTTTTCAATTC-3'; 4A1 (exon 59)
5'-GAATGGTGCACAGGAACTG-3'; 4B3 (exon 61)
5'-TCTGTACATGTCTATCACC-3'; 5B1 (exon 52)
5'-TACCCACATATCATGTTC-3'; 39A (intron 38)
5'-CATTTTTACTCAAACTATTG-3'; 39B (intron 39)
5'-TCTTAAATCCATCTTTCTCTA-3'; 59A (intron 58)
5'-AGGTCAACGGATCATCAAAT-3'; 59B (intron 59)
5'-TTAATTTTGGGTGTCACTC-3'; 65A (intron 64)
5'-TTAAACTGTTCACCTCACTGA-3'; 65B (exon 65)
5'-GTTAAAAATAAAGGCTAAAATA-3'.
1A1, 1A2, 1B1, 4A1 , 4B3, and 5B1 were derived from cDNA sequence
data of the ATM gene (GenBank accession no. U33841). PCR amplification
of the exons 39, 59, the coding part of exon 65, and the flanking
intronic regions from genomic DNA was performed according to
Vorechovsky et al14 using primer pairs 39A/B, 59A/B, and
65A/B.
Reverse-transcription PCR (RT-PCR) and single-strand conformation
polymorphism (SSCP) analysis were performed as described previously.18,25 Single-strand cDNA was synthesized using
random hexamers (GeneAmp RNA PCR System, Perkin-Elmer, Weiterstadt,
Germany). Six overlapping fragments covering 6.2 kb of the coding
region of the ATM transcript were amplified with primer sets
1A/B, 2A/B, 3A/B, 4A/B, 5A/B, and 6A/B. For SSCP analysis, RT-PCR
products were digested with restriction endonucleases and end-labeled
with T4 polynucleotide kinase in the presence of  -33P
deoxyadenosine triphosphate. Fragments were separated by
electrophoresis through nondenaturing 6% polyacrylamide gels
containing 5% glycerol (exclusively for runs at room temperature) in
0.5 × Tris-borate buffer. Electrophoresis was performed at room
temperature or at 4°C at 8 W for at least 10 hours. Gels were dried
and subjected to autoradiography.
Direct sequencing of PCR and RT-PCR products was performed by cycle
sequencing with dye terminator chemistry (ABI PRISM big dye
terminator cycle sequencing ready reaction kit, Perkin-Elmer). Sequencing reactions were run on a Perkin-Elmer ABI-377 automated sequencer.
To test whether the two heterozygote mutations identified in MCL-B were
localized on the same ATM transcript, RT-PCR products amplified
with primer set 5A/B were cloned into pT-Adv (AdvanTAge PCR Cloning
Kit, Clontech, Heidelberg, Germany). Insert DNA from individual clones
was amplified by colony PCR using the original PCR primers and PCR
conditions. Amplified DNA fragments were subsequently sequenced.
| |
RESULTS |
Mutations in malignant B-cell lymphomas with 11q deletions.
Based on FISH analysis, 23 malignant lymphomas of B-cell type (22 B-CLL
cases; one MCL case) with monoallelic deletions of chromosomal region
11q22-q23 were selected for mutation screening in the ATM gene.
ATM transcript was analyzed by RT-PCR amplification of a set of
six overlapping fragments representing exons 22-30, 29-36, 36-43, 42-51, 51-57, 56-65.25 This 6.2-kb part of the coding
region includes the protein domains, which are responsible for the
kinase function (exons 57-65) and the binding of c-Abl (exon 30), as
well as a postulated rad 3 homology domain (exons 32-42) and a leucine
zipper motif (exon 27).4,5,26,27 After digestion with
restriction endonucleases, the RT-PCR products were subjected to SSCP analysis.
Aberrantly migrating DNA fragments were found in five cases. Direct
sequencing of the corresponding RT-PCR fragments detected one
single-base deletion and four single-base substitutions as detailed in
Table 1. The deletion of one nucleotide in
B-CLL-A causes a frameshift after codon 2804 resulting in a truncation of the protein at this position and the loss of about 70% of the kinase domain (Fig 1A). In
B-CLL-B, a transition creates a new stop codon at position 3047, which
leads to the removal of the last 10 amino acids from the translation
product (Fig 1B). In three cases, amino acid substitutions were
detected. Two of them are predicted to alter the protein structure in
the PI-3-K domain (in B-CLL-D and B-CLL-E), the other one affected the
so-called rad 3 homology domain (in B-CLL-C). The nonmalignant cells
from B-CLL-B (Fig 1B), B-CLL-D, and B-CLL-E, obtained by skin biopsy, did not harbor the same nucleotide changes as the malignant cells, indicating a somatic, but not a germline origin of the mutations in all
three cases.
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| Fig 1.
Point mutations in the ATM gene in malignant
B-cell lymphomas with (A, B, C) and without (D) monoallelic deletions
of ATM. Mutations are indicated by arrowheads or by a bar. A,
B-CLL-A: SSCP analysis of a 242-bp restriction fragment derived
from the RT-PCR product containing exons 56-65 identified an aberrantly
migrating fragment. DNA sequence analysis of the respective fragment
showed 8412delA causing frameshift and truncation of the protein. DNA
sequences of PCR amplified exon 59 are shown. (B) B-CLL-B: SSCP
analysis of a 307-bp restriction fragment of the RT-PCR product
encompassing exons 56-65 and DNA sequence analysis of the corresponding
RT-PCR products identified the nonsense mutation 9139C>T
(Arg3047ter). Note that the amount of cells with an 11q22-q23 deletion
was 58% in the tumor sample, and therefore the signal intensity of the
normal allele was unusually high. DNA sequence analysis of exon 65 from
patient's germline DNA showed absence of the mutation in the germ
line. (C) MCL-A: The splice-donor site mutation in intron 59 (IVS59+1G>T), which causes skipping of exon 59 from the ATM
transcript and loss of 50 amino acids, was detected by DNA sequencing
of the RT-PCR fragment containing exons 56-65 and by sequencing of PCR
amplified exon 59 and its flanking intronic regions. The patient's
germ line DNA did not contain the mutation. (D) MCL-B: Cloning and
subsequent sequencing of RT-PCR fragments harboring exons 51-57 allowed
assignment of the two heterozygous mutations 7268A>G and
7250insGAA to two separate ATM transcripts. Thus, both alleles
were affected by two independent mutations.
|
|
In MCL-A, RT-PCR fragment 4 containing exons 56-65 showed a
significantly smaller size on agarose gels and presented a complete loss of exon 59 when sequenced directly (Fig 1C). Further genomic DNA
sequencing showed a G>T transversion at the first nucleotide of
intron 59, in the donor-splice junction of exon 59/intron 59, at
position 8418+1 (Table 1). According to the RT-PCR sequence data, this
nucleotide substitution obviously leads to complete skipping of the
in-frame exon 59 from the ATM transcript, which removes 50 amino acids from the kinase domain of the ATM protein. Sequence
analysis of genomic DNA from skin cells of this patient showed that
this splice-site mutation was not present in nonmalignant cells, indicating a somatic mutation origin (Fig 1C).
Mutations in malignant B-cell lymphomas without 11q deletions.
In addition to B-cell lymphomas with monoallelic 11q deletions, five
B-CLL cases and one MCL case without microscopically detectable
deletions of chromosome bands 11q22-q23 were searched for ATM
mutations (by SSCP and sequence analysis). In one of the two B-CLLs
with a translocation approximately 2 Mbp distal from the ATM gene
locus, a heterozygous missense mutation in the rad 3 homology domain
was identified (B-CLL-F; Table 1). In B-CLL-G, a nucleotide
substitution in one allele lead to an amino acid replacement at
position 2420 (Table 1). In the same protein region, two heterozygous
mutations were detected in MCL-B (Fig 1D): a trinucleotide insertion
incorporated an additional lysine at position 2419 and a single-base
substitution caused an amino acid exchange at position 2423. Cloning
and subsequent sequencing of RT-PCR fragments, which covered both
mutational sites allowed the assignment of the mutations to separate
ATM transcripts, thus indicating two independent mutation
events affecting both alleles in MCL-B (Fig 1D).
Identification of a common genetic polymorphism.
In contrast to the aforementioned point mutations, in our series one
amino acid substitution was observed more than once: Asp1853Asn
(5557G>A) was found in six of the 29 tumor samples analyzed (21%;
B-CLL-B, B-CLL-E, B-CLL-H, B-CLL-J, B-CLL-K, B-CLL-L). An
estimation of the germline status by sequence analysis of genomic DNA
from skin cells was possible in four cases (B-CLL-B, B-CLL-E, B-CLL-J,
and B-CLL-K). In B-CLL-J, the 5557A allele was absent in the
nonmalignant cells indicating its somatic origin, whereas in the other
three patients the 5557A allele was already present in the germ line in
a heterozygous form. Interestingly, in one of those cases (B-CLL-B),
the 5557A allele was apparently lost during tumorigenesis, as it was
only detectable in a low amount in the tumor sample corresponding to
the amount of cells without 11q deletion in the specimen (concluded
from sequence analysis of both genomic DNA and RT-PCR products). The
analysis of 50 samples from healthy controls detected the 5557A allele
in 11 samples (22%). Nine samples were heterozygous and two samples
were found to be homozygous for 5557A, resulting in an allele frequency
of 0.13 in the population studied. Because of the similar frequency of
Asp1853Asn positive tumor samples and carriers in the control population, this variant has to be considered a common polymorphism, which seems not to be disease associated. In a recent study of breast
cancer patients in Britain, 5557A was also identified as polymorphic
allele.28 The single-base substitution 5558A>T in B-CLL-F, which affected the same codon, but caused a different amino
acid exchange (Asp1853Val), was not found in the 50 controls and is
therefore compatible with the definition of a pathogenic mutation.
| |
DISCUSSION |
Two lines of evidence emphasize the pivotal role of a tumor suppressor
gene localized in 11q22-q23 for the leukemogenesis of B-CLL: (1)
deletion of this chromosomal region is one of the most frequent
chromosome aberrations in this disease.24 (2) The 11q22-q23
deletions have a strong clinical impact, as they define a subset of
B-CLL characterized by extensive lymph node involvement, rapid disease
progression, and poor survival.24 In the current study, a
series of malignant B-cell lymphomas, mostly B-CLLs, with deletions of
one copy of chromosome bands 11q22-q23 were analyzed. In six of the 23 analyzed cases, the ATM gene was found affected by a point mutation in
the nondeleted allele. Besides those, there was one B-cell lymphoma
without 11q deletion, but with mutations in both ATM alleles.
The inactivation of both gene copies indicates a pathogenic role of
ATM in sporadic B-cell tumors. The identified mutations
resulted in aberrant transcript splicing, premature truncation of the
protein, or alteration of amino acids. Fifty percent of the mutations
affected the PI-3-K domain, which is highly conserved among ATM-related
proteins4,5 and crucial for the protein kinase activity of
ATM.29,30 Interestingly, three of those mutations
correspond to disease-causing mutations in A-T patients and/or
mutations associated with T-PLL underlining the pathogenic character of
the mutations: (1) the truncation mutation Arg3047ter has been
described as an A-T allele9,31-33 and as a mutation in
T-PLL19 causing considerable impairment of the protein
phosphorylation function of ATM29; (2) the splicing defect
caused by IVS59+1G>T resembles A-T mutations, which cause skipping of
the affected exon 5925,32,34;(3) the missense mutation
Arg3008His replaced the same conserved amino acid as Arg3008Cys in two
independent T-PLL cases.18,21
The PI-3-K domain was recently shown to mediate phosphorylation of p53
in response to DNA damage.29,30 Therefore, mutational inactivation of the kinase domain likely affects the p53 mediated control of the cell cycle and response to DNA damage. Constitutional ATM deficiency in cells of A-T patients (for review, see Lavin and
Shiloh2 and Jeggo et al3) and
atm /- mice35-37 was found to
lead to dysregulation of apoptosis and cell-cycle check point control,
as well as to defects in DNA recombination. These cellular defects are
considered to be causative for the development of T-cell lymphomas in
atm/- mice36,38 and lymphoid
tumors of both the T- and B-cell lineage in A-T patients.11
It is conceivable that somatic ATM inactivation in lymphocytes
may result in similar cellular defects, which may contribute to T- and
B-cell leukemogenesis in non-A-T patients.
Here, we demonstrate that somatic disruption of the ATM gene occurs not
only in sporadic T-PLL,18-21 but is also common for B-cells
of malignant B-cell lymphomas, in particular, B-CLLs. Two very recent
studies analyzing ATM gene mutation and ATM protein levels reported
similar evidence for the role of ATM in B-CLL.39-41 However, Stankovic et al40 could not observe loss of
heterozygosity of the respective genomic region in a subset of tumors
with impaired ATM expression, a fact that could be explained by the
existence of a second B-CLL associated gene in the critical genomic
segment in 11q.
The mutation frequency observed in our study exceeds by far the
expected value of random mutations taking the A-T heterozygote frequency of about 1% in the general population42,43 into
account. Therefore, ATM is probably the tumor-suppressor gene
in 11q22-q23, whose inactivation is responsible for an aggressive
course of B-CLL. There are several reasons why we did not observe
ATM point mutations in a higher proportion of the cases
analyzed: (1) mutation analysis focused on a 6.2-kb part of the coding
region encompassing the kinase domain, the c-Abl binding site, the rad3
homology region, and a leucine zipper motif. Mutations could also
reside, however, in the N-terminal region of ATM, which was recently
shown to interact with  -adaptin,44 or in the
nontranslated regions or the promoter region impairing gene expression.
(2) While we used a modified SSCP method, also known as restriction
endonuclease fingerprinting (REF), which is of considerably enhanced
efficiency,45 it is still possible that we missed
mutations. (3) The commonly deleted region in 11q22-q23 is 2 to 3 Mbp
in size and contains besides ATM several other
genes.23 At this point, it cannot be excluded that a second
gene with pathogenic function for B-CLL exists in this region (see also above).
For four patients with ATM point mutations in the tumor cells,
an assessment of the ATM germline status was possible. Absence of the mutations in the nonmalignant cells in all four cases indicated a somatic origin of the mutations. However, others reported ATM germline mutations in some of the B-CLL patients carrying ATM mutation40,41 showing the existence of genetic
predisposition to B-CLL.
| |
ACKNOWLEDGMENT |
The authors gratefully acknowledge Ralf Klären, Irina Idler, and
Markus Scheuermann for their technical assistance.
| |
FOOTNOTES |
Submitted December 10, 1998; accepted March 2, 1999.
Supported by the Wilhelm-Sander-Stiftung (97.003.1), the Deutsche
Krebshilfe (10-1289-StI), 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 Peter Lichter, PhD, Abteilung
"Organisation komplexer Genome" (H0700), Deutsches
Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg,
Germany; e-mail: p.lichter{at}dkfz-heidelberg.de.
| |
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TOP
ABSTRACT
INTRODUCTION