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From the Department of Pathology,*
Centre
Hospitalo-Universitaire Purpan, Toulouse, France; UPCM-UPR 2163
CNRS,
Purpan, Centre Hospitalo-Universitaire,
Toulouse, France; LRF Immunodiagnostics Unit,
Department of Cellular Science, John Radcliffe Hospital, Oxford, United
Kingdom; and the Department of Experimental
Oncology,§
St. Jude Children’s Research
Hospital, Memphis, Tennessee
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because NPM is a "housekeeping" gene, the NPM-ALK chimeric protein is constitutively expressed from the NPM promoter, leading to the ectopic overexpression of the ALK catalytic domain.6 In addition, the NPM protein normally forms homo-oligomers, and it has been demonstrated that the NPM-ALK chimeric protein is able to form dimers both with normal NPM and with itself.8 It is thought that NPM-ALK homodimerization mimicks ligand-induced receptor cross-linking and is thus responsible for the transphosphorylation and activation of ALK.8 This constitutive activation of the ALK tyrosine kinase domain seems to play a role in the malignant transformation of lymphoid cells in ALCLs.8,9,10 However, we have recently shown that genes other than NPM could provide a promoter to drive the expression of the ALK tyrosine kinase domain, inasmuch as an ALK product has been found in a case of ALCL associated with a variant (1;2)(q25;p23) translocation.4,11,12 In addition, expression of the full-length ALK receptor protein, by a mechanism that remains to be elucidated, has been reported in a subtype of B-cell lymphomas that lack the (2;5) translocation.13
In normal mouse tissues, mRNA encoding the Alk receptor has been reported in neural cells,14,15 and it has been suggested that Alk plays a role in the development of the embryonic nervous system.14 However, published studies have focused mainly on Alk expression in the mouse, and the purpose of the present study was to examine normal human tissues and a variety of human tumors and cell lines, with emphasis on neuroblastomas, for the presence of ALK transcripts and protein. Previous studies have described tyrosine kinase receptor expression in neuroblastomas.16,17 A number of recently published studies have identified the expression of the TRK neurotrophin receptor tyrosine kinase in neuroblastoma.18 In addition, receptors of the TRK family have been shown to correlate with the behavior of human neuroblastomas.19 Thus we investigated the expression of ALK, which shares significant homology to the TRK receptors, in primary neuroblastomas to evaluate the prognostic significance of ALK expression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Fifty-six human neoplastic cell lines were investigated, all of
which were obtained, unless otherwise indicated, from the American Type
Culture Collection. Lymphoid cell lines comprised CEM, HSB-2, and
Jurkat (acute T-lymphoblastic leukemias); LIB (large B-cell lymphoma,
our laboratory); and SU-DHL-1 (t(2;5)-positive anaplastic lymphoma,
kindly provided by Dr M. L. Cleary, Stanford University Medical
Center, Stanford, CA). Nonlymphoid lines comprised 11 epithelial cell
lines, 11 mesenchymal cell lines, and 29 cell lines of neural or
neuroectodermal origin (Table 1)
. The NB
neuroblastoma cell lines (all derived at St. Jude Children’s Research
Hospital) have previously been described.20
The
t(2;5)-positive SU-DHL-1 anaplastic lymphoma cell line and the Rh30
rhabdomyosarcoma cell line6
were used, respectively, as
positive controls for NPM-ALK and full-length ALK. Tumors were
available as cultured cell lines or as frozen specimens of neoplasms
grown in SCID or nude mice.
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All tissues were studied as fresh-frozen biopsy samples.
Lymphoid Tissues
Five nonneoplastic lymphoid tissues (four reactive lymph nodes, one tonsil), one thymoma, and 35 lymphomas of different categories were tested. The latter included eight cases of anaplastic large cell lymphoma that have been reported previously.4,11 These cases coexpressed CD30 and EMA antigens and were of T or null phenotype.21 In four cases, the chimeric NPM-ALK transcripts were detected using reverse transcriptase-polymerase chain reaction (RT-PCR) with 5'NPM and 3'ALK primers, as previously described,4 and/or by immunostaining with ALK1 antibody.11 The four remaining cases showed no evidence of the t(2;5). Ten cases of nonanaplastic large-cell lymphoma of T phenotype and six cases of B-cell lymphoma (one follicular lymphoma, five diffuse large B-cell lymphomas) were also investigated. The 11 remaining cases were lymph nodes involved in Hodgkin’s disease (seven cases of nodular sclerosing type, four cases of mixed cellularity type).
Nonlymphoid Tissues
One salivary gland, two thyroid glands, one glioblastoma, one
colonic adenocarcinoma, and 24 neuroblastomas were investigated. Most
of the neuroblastoma cases were obtained from the Pediatric Oncology
Group (POG) Neuroblastoma Tumor Bank, after protocol approval (Table 3)
. Histological analysis in each case revealed a homogeneous
population of tumor cells. These comprised a cohort of 20 tumors chosen
to represent the spectrum of neuroblastoma subgroups by disease stage,
age, N-myc copy number, and DNA ploidy and were from
uniformly treated patients. Included in this cohort were tumors with
bad (N-myc amplification, age >1 year, stage III or IV,
diploid DNA content in patients 
1 year), as well as favorable
(absence of N-myc amplification, age 1 year; stage I, II,
or IVS; hyperploid DNA content in patients 1 year) prognostic
indicators. The four remaining neuroblastoma cases were selected from
the tissue bank of one of the investigators (GD).
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ALK proteins were detected on frozen sections or cytospin preparations by monoclonal antibody ALK1, which recognizes the intracellular domain of ALK, as previously described.11
RNA Extraction and cDNA Preparation
Total RNA was obtained from frozen cell pellets (10 x 106 cells) or from 20 5-µm-thick frozen sections of tumor fragments, using the RNeasy Midi kit (Qiagen SA, Courtaboeuf, France). Reverse transcription was performed at 42°C on either 1 µg total RNA, using an ALK specific oligonucleotide primer (see below) and AMV reverse transcriptase for 90 minutes, as recommended by the enzyme manufacturer (Boehringer Mannheim France SA, Meylan, France), or on 5 µg total RNA, using an oligo(dT) primer and Superscript II RT (Stratagene, La Jolla, CA).
RT-PCR Analysis
cDNA quality was checked either by amplifying a 461-bp fragment of
ß-actin, between primers ACT1: 5' TCA TGT TTG AGA CCT TCA A 3' and
ACT2: 5' GTC TTT GCG GAT GTC CAC G 3', or a product of 450 bp, using
G3PDH PCR primers (Clontech, Palo Alto, CA). The presence of
ALK mRNA was investigated using primer pairs chosen from the
ALK cDNA sequence13
(Figure 1)
:
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ALK-TK3: 5' ATG GAC CCA CCC AAG AAC TGC CC 3' (position 4953–4975) and ALK-CO2: 5' CAG TAC AGC TTC CCT CCA GCC CC 3' (position 5532–5510), which amplify a 580-bp fragment containing the sequence encoding the carboxy-terminal residues of the kinase catalytic domain and a portion of the carboxy-terminal tail, the region previously used as an immunogen to generate the monoclonal antibody ALK1.11
S-hu-18 (5' AAG CAC CAG GAG CTG CAA 3') (position 4095–4112) and AS-hu-18 (5' GCT TGG GTC GTT GGG CAT 3') (position 4340–4323), chosen to span the intron located between the exons encoding the juxtamembrane domain and the amino-terminal portion of the kinase domain of human ALK to distinguish unequivocally products derived from genomic DNA, as opposed to the cDNA created by reverse transcription. These primers yield a PCR product of 246 bp, using human ALK cDNA as a template.
ALK-EC1: 5' CCA TCT CCT TCT CCT GAT TAT TTT 3' (position 1611–1634) and ALK-EC2: 5' CAC TGC AGA CAA GCT GGG GTT 3' (position 2162–2142), yielding a 552-bp PCR fragment of the extracellular portion of the ALK mRNA.
The strategy consisted of a two-step PCR amplification, using the same primers. The first round was performed on total cDNA (corresponding to 0.2 µg of total RNA), using an automated thermal cycler (Hybaid; TR3 Omnigene, Teddington, UK), with 300 µmol/L of each primer, 0.25 U of Goldstar DNA polymerase (Eurogentec, Liège, Belgium), and 500 µmol/L deoxynucleotide triphosphates in PCR buffer containing 1.5 mmol/L MgCl2 in a final volume of 25 µl. After an initial denaturation of 2 minutes at 95°C, 30 cycles of amplification were performed as follows: 95°C for 45 seconds, 68°C for 45 seconds, and 72°C for 20 seconds. The second amplification was performed under the same conditions, using 1 µl of the first-round PCR product as a template. PCR products were electrophoresed on 1.2% agarose gels and visualized with ethidium bromide staining.
PCR Sensitivity for ALK mRNA Detection
To test the sensitivity of our PCR method with the ALK2S and ALK0 primers, we used as the target a purified ALK cDNA fragment containing the sequence located between this primer pair. We then performed a two-step amplification with the ALK2S and ALK0 primers, using serial dilutions of this cDNA of known molecular concentration (measured by spectrophotometric analysis). Results were analyzed by electrophoresis on an agarose gel.
Semiquantitative RT-PCR Analysis of ALK mRNA in Cell Lines and Neuroblastoma Cases
Semiquantitation of the level of specific cDNA targets in six cell
lines and four neuroblastomas was performed by limiting dilution (Table 2)
. Tenfold sample dilutions were
prepared in Tris-EDTA buffer containing salmon sperm DNA (5 µg/ml) as
a carrier, and each dilution was submitted to a two-stage PCR, using
the ALK2S and ALK0 primers, followed by agarose gel analysis. We could
thus determine the highest dilution giving a positive amplification,
and this was compared to the dilution range of the two reference cell
lines (Rh30 and SU-DHL-1).
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Cell pellets containing 5 x 106 cells, or small fragments of solid tumors were prepared as previously described.11 Cytoplasmic extracts containing 20 µg protein (or 100 µg for neuroblastoma cases), as determined by Bradford assay,22 were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in a 7.5% gel under reducing conditions. Proteins were transferred to Immobilon (polyvinylidene difluoride) membranes (Millipore UL, Watford, UK) by semidry electroblotting, and the membranes were then blocked by incubation in phosphate-buffered saline containing 5% nonfat milk and 0.1% Tween 20 for 30 minutes at 37°C. The membranes were then incubated for 30 minutes at room temperature with ALK1, with rabbit polyclonal anti-ALK#11,15 or with a negative control antibody (MR12, a mouse anti-rabbit Ig antibody, prepared in the author’s laboratory). After a wash in phosphate-buffered saline containing 0.1% Tween 20, sites of antibody binding were detected by incubation with horseradish peroxidase-conjugated goat anti-mouse (diluted 1:1000) or anti-rabbit (1:500) immunoglobulins (Dako, Glostrup, Denmark), before chemiluminescent detection with Amersham ECL reagents (Amersham International, Little Chalfont, UK).
In Vitro Kinase Assay
Fragments of solid tumors or cell pellets (5 x 106 cells) from the CEM, Jurkat, HSB-2, LIB, Calas, NCI-H69, SK-N-SH, SK-H-MC, Rh30, and SU-DHL-1 cell lines were suspended in the lysis buffer, as previously described.23
After a brief spin, the precleared lysate was added to 25 µl of
protein G-Sepharose preloaded with either monoclonal
anti-phosphotyrosine antibody 4G10 (Upstate Biotechnology, Lake Placid,
NY) or antibody ALK1 and rotated at 4°C for 1 hour. The Sepharose
beads were washed three times in lysis buffer and twice in kinase
buffer (20 mmol/L HEPES (pH 7.4), 0.1% Brij 96) before incubation for
15 minutes in kinase buffer containing 10 mmol/L
MnCl2, 10 mmol/L NaF, 1 mmol/L
Na3(VO4), and 5 µCi
[
-32P]ATP (Amersham International). The
reaction was stopped by the addition of 2x SDS sample buffer and
separated on a 10% gel by SDS-PAGE. The gels were then dried and
subjected to autoradiography.
Sequential Immunoprecipitation and Western Blotting Studies
Supernatants from the SU-DHL-1 anaplastic large cell lymphoma cell line and the two neuroblastoma cell lines SK-N-MC and SK-N-SH were prepared using the tyrosine kinase assay lysis buffer as described above. After preclearing with protein G-Sepharose, the lysates were rotated for 2 hours at 4°C with protein G-Sepharose preloaded with one of the following antibodies: ALK#11, ALK1, or anti-phosphotyrosine. After washing, the pellets were resuspended in 2x SDS sample buffer and resolved by SDS-PAGE. Proteins were electrophoretically transferred to Immobilon and stained using one of the following antibodies: ALK#11, ALKc (kindly provided by B. Falini),24 anti-phosphotyrosine, or MR12, as described above.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, Tables 1 and 2
)
Positive amplification was detected as expected in the four cases
of ALCL and the SU-DHL-1 cell line that carried the t(2;5) anomaly,
using only the two primer pairs (see Materials and Methods)
corresponding to the ALK cytoplasmic domain. The rhabdomyosarcoma cell
lines (Rh30, RD) known to express full-length ALK showed positive
amplification for both extracytoplasmic and extracellular
ALK domains. However, five neuroblastoma lines, four
neuroblastoma cases (N1, N2, N3 and N4) (Figure 2)
, the small cell lung carcinoma cell
line NCI-H69, and the melanoma cell line Calas also gave positive
results with these primers. No amplification was obtained from any of
the lymph nodes, normal tissues, or other lymphomas studied.
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It was possible to detect approximately 10 molecules of cDNA
(Figure 3)
when the ALK2S and ALK0
primers (corresponding to sequences from the juxtamembrane and
catalytic domains of the ALK protein) were used in a two-stage PCR
method. Semiquantitative RT-PCR analysis for ALK mRNA with
this primer pair (Table 2)
showed that the SK-N-SH and SK-N-MC (Figure 4)
neuroectodermal cell lines expressed
levels of ALK mRNA comparable to those found in the
t(2;5)-positive SU-DHL-1 (Figure 5)
and
the Rh30 cell lines. Intermediate or low levels were found in the
NCI-H69 (small cell carcinoma) (Figure 4)
and Calas (melanoma) cell
lines (Table 2)
, and the four neuroblastoma tumors tested showed
intermediate to high ALK mRNA levels.
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. The
slightly lower sensitivity achieved with this primer pair was
interpreted as reflecting the greater sequence encompassed by these
primers and the mRNA polyA tail. Immunostaining
Two neuroectodermal cell lines (SK-N-SH and SK-H-MC) (Table 2)
and
one of the four cases of neuroblastoma (N4) (Figure 6)
showed weak immunostaining on both
cryostat and paraffin sections. Although ALK is a receptor anchored
through the membrane, the staining seemed to be cytoplasmic, as already
reported in normal cells in the central nervous system.11
In contrast, as expected from previous results, the t(2;5)-positive
SU-DHL-1 cell line, the four cases of t(2;5)-positive ALCLs, and the
Rh30 rhabdomyosarcoma cell line (expressing full-length ALK protein)
were all clearly positive for ALK protein.
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Bands of 200 kd (ALK) and 80 kd (NPM-ALK) were found, as expected,
in lysates of, respectively, the Rh30 and SU-DHL-1 cell lines (Table 2
and Figure 7
). Full-length 200-kd ALK
receptor protein was also detected in one neuroectodermal cell line and
nine neuroblastoma cell lines (Table 1)
, two of which are shown in
Figure 7
. The 200-kd full-length receptor was also observed in 19
neuroblastoma cases (Table 3
and Figure 8
). No correlation was evident between
ALK receptor expression levels and known neuroblastoma prognostic
indicators such as N-myc amplification, age of patient,
stage, or DNA content (Table 3)
.
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In Vitro Tyrosine Kinase Assay (Table 2)
As expected, proteins immunoprecipitated from the t(2;5)-positive
SU-DHL-1 cell line with either anti-ALK or anti-phosphotyrosine and
subjected to this assay showed a strong band of 80 kd, representing
autophosphorylated NPM-ALK (Figure 9)
. A
strong 200-kd band representing autophosphorylated ALK was detected in
proteins immunoprecipitated from the Rh30 and SK-N-SH cell lines with
anti-ALK (Figure 9a)
. A 200-kd protein was also weakly present in
anti-phosphotyrosine immunoprecipitates (Figure 9b)
from these cell
lines. Proteins immunoprecipitated from the SK-N-MC cell line with
anti-ALK (but not with anti-phosphotyrosine) showed a weak
phosphorylated 200-kd band (Figure 9a)
. No phosphorylated proteins were
detected by the in vitro kinase assay in ALK
immunoprecipitates of the CEM, HSB-2, Jurkat, or LIB lymphoid cell
lines.
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Phosphorylated 80-kd NPM-ALK protein was detected in
both the ALK and the phosphotyrosine immunoprecipitates from the
SU-DHL-1 cell line (Figure 10)
. In
contrast, the 200-kd ALK protein present in the SK-N-MC and SK-N-SH
cell lines could only be detected by Western blotting of
immunoprecipitates obtained with anti-ALK (Figure 10a)
but not with
anti-phosphotyrosine immunoprecipitates (Figure 10a)
. This indicated
that the full-length protein present in these cells was not strongly
phosphorylated. In keeping with this interpretation, no reactivity was
observed when anti-ALK immunoprecipitates from these two
neuroectodermal cell lines were Western blotted with
anti-phosphotyrosine (Figure 10b)
. Phosphorylated proteins other than
ALK, however, were present in the phosphotyrosine immunoprecipitates
from these two neuroectodermal cell lines (Figure 10b)
. Comparable
results were obtained using rabbit anti-ALK#11 to either
immunoprecipitate ALK or to detect ALK proteins by Western blotting
(not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent studies using Northern blotting analysis, in situ hybridization, and/or immunohistochemistry suggest that ALK expression is normally restricted to the nervous system in both the human and mouse.11,14,15 To date, there is little information on the presence of ALK mRNA in normal lymphoid tissues, although spleen, thymus, peripheral blood leukocytes, B-lymphoblastoid cell lines, and various t(2;5)-negative leukemia-lymphoma cell lines have been found to be negative for the ALK mRNAs6 or ALK proteins.3,4,11 It is therefore generally accepted that the ALK promoter is silent in normal lymphoid cells and that the expression of a truncated ALK protein under the control of the NPM promoter occurs ectopically in malignant lymphoid cells bearing the t(2;5)(p23;q35) translocation.
The results from the present study are consistent with this belief
because, with the exception of ALCLs, mRNAs encoding for ALK proteins
were not detectable in any normal or neoplastic hematopoietic tissue
tested. The most interesting finding was the detection of
ALK mRNA and ALK protein in cell lines and tumors of neural
origin. In the SK-N-SH and SK-N-MC neuroectodermal cell lines, and in
the Rh30 rhabdomyosarcoma line (used as a positive control for
full-length ALK expression), ALK mRNAs were
detected using primers corresponding to both the cytoplasmic and the
extracellular domains of the receptor (see Table 2
and Figure 1
).
Semiquantitative RT-PCR indicated that the levels of ALK
mRNAs were comparable to those found in the Rh30 cell line. This
evidence for the expression of ALK in these cell lines was confirmed by
positive immunohistochemical staining (albeit weak) and by Western
blotting, which revealed a 200-kd band corresponding to full-length ALK
protein. The latter technique also revealed ALK protein in eight other
neuroblastoma or neuroectodermal lines that were not studied by RT-PCR.
Thus evidence was obtained for ALK expression in neuroblastoma cells by
three independent techniques (RT-PCR, Western blotting, and
immunohistochemistry). These data are in agreement with recent reports
of ALK mRNAs and ALK protein in parts of the central and
peripheral nervous system in both embryonic and adult
mice.14,15
Although in vitro kinase assays of proteins immunoprecipitated with anti-ALK from lysates of the SK-N-SH, SK-N-MC, and Rh30 cell lines revealed phosphorylation of full-length ALK, sequential immunoprecipitation followed by immunoblotting (anti-ALK followed by anti-phosphotyrosine or vice versa) provided no evidence of significant levels of endogenously autophosphorylated ALK. This is in contrast to the high level of constitutive phosphorylation of NPM-ALK observed here and in previous reports.8,9 These results suggest that full-length ALK protein may not be enzymatically active (and hence may not be involved in oncogenic transformation) in these cell lines and support the view that its presence may be a physiological rather than an oncogenic phenomenon.
We have demonstrated for the first time the presence of ALK mRNA and/or ALK protein in fresh primary neuroblastomas (22/24 cases). However, no correlation between known neuroblastoma prognostic factors and the level of ALK expression was identified. This is not the first report of tyrosine kinase receptor expression in neuroblastomas.16-18 The expression of TRKA and TRKC has been shown to correlate with a favorable patient outcome, whereas the expression of TRKB is associated with unfavorable, aggressive tumors.18,19,25 Highly malignant neuroblastomas that express TRKB also produce its cognate ligand, BDNF, and it therefore appears that these tumor cells are stimulated to grow in an autocrine fashion. The mechanisms by which TRKA and TRKC expression contributes to a better prognosis in neuroblastoma are unclear, although it is thought that receptor activation by their ligands, NGF and NT3, respectively, may produce a more differentiated tumor cell phenotype. Consistent with this hypothesis, overexpression of TRKA in neuroblastoma cell lines enhances NGF-induced differentiation both in vitro and in vivo.26 These data suggest the possibility that other neural-specific receptor tyrosine kinases could also be important in the development and progression of neuroblastoma. In this study, the expression in many human neuroblastomas of ALK, a receptor tyrosine kinase with significant homology to the TRK receptors, suggests that this neural-specific receptor may play an as yet unidentified role in the natural history of these tumors.
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Acknowledgements |
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Footnotes |
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Supported by the Projet Hospitalier de Recherche Clinique (PHRC98), the GELA (Groupe d’Etude des Lymphomes de l’Adulte), the Ligue Contre le Cancer de la Haute Garonne, the Ligue Contre le Cancer de l’Aveyron, the Ligue Contre le Cancer du Gers, the Leukemia Research Fund (grant number 9646, UK), National Cancer Institute grant CA 69129 (SWM), Cancer Center Support (CORE) grant CA 21765, and the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children’s Research Hospital.
Accepted for publication January 24, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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