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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 362-364
t(1;2)(q21;p23) and t(2;3)(p23;q21): Two Novel Variant Translocations
of the t(2;5)(p23;q35) in Anaplastic Large Cell Lymphoma
By
Andreas Rosenwald,
German Ott,
Karen Pulford,
Tiemo Katzenberger,
Joachim Kühl,
Jörg Kalla,
M. Michaela Ott,
David Y. Mason, and
Hans Konrad Müller-Hermelink
From the Pathologisches Institut and Kinderklinik, University of
Würzburg, Würzburg, Germany; and the University Department
of Cellular Science, John Radcliffe Hospital, Oxford, UK.
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ABSTRACT |
Cytogenetic investigations in two cases of anaplastic large cell
lymphoma (ALCL) showed novel variants of the classical (2;5)(p23;q35) translocation, namely a t(1;2)(q21;p23) and a t(2;3)(p23;q21). The
tumor cells in both cases gave positive immunohistochemical labeling
for ALK protein (with both monoclonal and polyclonal antibodies),
demonstrating that these translocations induce aberrant expression of
this kinase and suggesting that genes other than NPM can
activate the ALK gene in ALCL. These two cases were shown by an
in vitro kinase assay to express ALK kinases (104 kD and 97 kD,
respectively), which differed in size from the classical NPM-ALK fusion
product (80 kD). Moreover, ALK expression was confined to the cytoplasm
of the tumor cells in each case, supporting the hypothesis that the
observed nuclear localization of NPM-ALK in classical ALCL is not the
site of oncogenic activity of the ALK kinase.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
ANAPLASTIC LARGE cell lymphoma (ALCL),
first described by Stein et al,1 constitutes a subgroup of
non-Hodgkin's lymphoma characterized by unusual morphologic features
and expression of the CD30 (Ki-1) antigen. Thirty percent to 40% of
nodal ALCL carry the reciprocal t(2;5)(p23;q35) chromosomal
translocation.2-4 This genetic abnormality juxtaposes the
NPM gene at 5q35 to the ALK gene at 2p23,5
leading to the generation of a novel chimeric NPM-ALK 80-kD kinase. ALK
protein is not expressed in normal lymphocytes, and monoclonal and
polyclonal anti-ALK antibodies (ALK1 and p80NPM/ALK) have
therefore been widely used to provide immunohistochemical evidence for
the presence of the NPM-ALK fusion protein in lymphoma cells.6,7
Two cases of ALCL have been reported recently in which a positive
immunohistochemical reaction for ALK protein was found in the absence
of the t(2;5)(p23;q35) (as detected by classical
cytogenetics).8,9 These cases were shown to carry variants
of the classical t(2;5), namely a t(1;2)(q25;p23) and an
inv(2)(p23q35). One further variant translocation, a t(2;13)(p23;q34),
has been described by Sainati et al,10 although no
immunohistochemical data are available on ALK expression.
We here report on two novel variant translocations in ALCL and
additional immunohistochemical and in vitro kinase assay studies.
| |
MATERIALS AND METHODS |
Patients.
Patient 1 was the 13-year-old boy D.F. who showed painful enlargement
of cervical, axillary, and inguinal lymph nodes in June 1997. After
diagnosis of a CD30+ ALCL of T-cell phenotype, he underwent
chemotherapy according to the German NHL-BFM'95 protocol (group
III/K3).11 After the final cycle the patient has remained
in complete remission without symptoms.
A lymph node biopsy specimen obtained from patient 2 (10-year-old girl
S.N.) in July 1994 showed a CD30+ ALCL of null cell
phenotype. After initial chemotherapy (German NHL-BFM'90
protocol11) resulting in complete remission, a relapse occured in November 1995. Autologous bone marrow transplantation was
performed in December 1995, and since then she is in complete remission.
Immunohistochemical and cytogenetic studies.
Immunohistochemical investigations on lymph node biopsy specimens
included B- and T-cell markers, CD30 (BerH2), EMA, TIA-1, and the
p80NPM/ALK 6 and ALK17 antibodies.
Cytogenetic analysis was performed on unstimulated short-term cultures
of tumor tissue. Metaphases were stained by a conventional trypsin-Giemsa technique and evaluated according to the ISCN
guidelines.12
In vitro kinase assay.
Frozen tissue sections were subjected to an in vitro kinase assay
technique that is detailed elsewhere.13 A frozen tumor of
an ALCL-derived t(2;5)+ cell line SU-DHL-1 grown in
severe combined immunodeficient (SCID) or nude mice and normal tonsils
was used as positive and negative control.
| |
RESULTS AND DISCUSSION |
Histological evaluation of the lymph node biopsy specimen from patient
D.F. identified an ALCL of T-type with the tumor cells being positive
for CD5, CD30, and TIA-1 and exhibiting strong cytoplasmic staining for
ALK protein (with both the polyclonal antiserum p80NPM/ALK
and the monoclonal antibody ALK1; Fig 1a).
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| Fig 1.
(a) Section of a paraffin-embedded lymph node from
patient D.F. stained for ALK1 expression (alkaline
phophatase-technique). Large pleomorphic tumor cells show marked
cytoplasmic but no nuclear immunostaining. (b) G-banded partial
karyotype of patient D.F. exhibiting the translocation t(1;2)(q21;p23)
(arrows). (c) G-banded partial karyotype of patient S.N. showing the
t(2;3)(p23;q21) (arrows) and, additionally, a +del(3)(p21).
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Cytogenetics showed a karyotype of 46,XY,t(1;2)(q21;p23)[12]/92,XXYY,
t(1;2)(q21;p23)x2[4]/46,XY[1] (Fig 1b).
The lymph node biopsy specimen of S.N. led to the diagnosis of an ALCL
of null cell phenotype. Again, strong cytoplasmic staining was noted
for ALK protein (not shown). The karyotype, obtained from conventional
cytogenetics, was: 47,XX,t(2;3)(p23;q21),+del(3)(p21)[5]/46,XX[3] (Fig 1c).
In the in vitro kinase assay, the most prominent phosphorylated
proteins were a 104-kD band in the tumor from D.F. and a 97-kD band in
cells from S.N. (for details see Fig 2).
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| Fig 2.
Results from an in vitro kinase assay. Proteins were
extracted from cryostat tissue sections, immunoprecipitated with
anti-ALK, and incubated with radioactive kinase substrate. The samples
were then resolved using sodium dodecyl sulfate-polyacrylamide gel
electrophoresis followed by autoradiography. Phosphorylated proteins of
97 kD and 104 kD were detected in tumor tissue from patients S.N. and
D.F., respectively. 80-kD phosphorylated NPM-ALK was present in the
t(2;5)+ cell line SU-DHL-1. No ALK proteins were
present in the tonsil lysates used as negative controls.
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The t(2;5)(p23;q35) is regarded as a critical step in the genesis of
nodal ALCL leading to the generation of a chimeric 80-kD NPM-ALK
protein that is thought to cooperate in malignant transformation by
aberrant activation of its ALK kinase domain.14-16 There is now clear evidence that the NPM-ALK fusion protein is directed from the
cytoplasm to the nuclei of the tumor cells via heterodimerization with
normal NPM.15,16 This results in the characteristic
staining pattern for NPM-ALK in cells exhibiting the t(2;5)(p23;q35),
in which both the nuclei and cytoplasm are labeled.7,16,17
However, in a minority of ALCL cases, ALK protein expression is
restricted to the cytoplasm of tumor cells.17,18 A possible interpretation of this staining pattern is the presence of chromosomal abnormalities affecting the ALK gene but not involving
NPM, and there is direct evidence for this in the report of a
cytoplasmic distribution of ALK protein in an ALCL bearing a
t(1;2)(q25;p23).7,16 Moreover, an ALK fusion protein in
which NPM is replaced by a TPR sequence19 is capable of
transforming cells in vitro and in vivo but is expressed only in the
cytoplasm of transfected COS cells.15,16
These results indicate that mechanisms other than the classical t(2;5)
can lead to the activation of the ALK gene and that such cases
should be recognizable because of their `cytoplasm-only' pattern of
ALK expression. Our two cases of ALCL carrying novel variant
translocations support this suggestion. Furthermore, it was possible to
show using an in vitro kinase assay that these variant translocations
gave rise to ALK protein which differed in size from classical NPM-ALK
(80 kD).5-7 The tumor carrying the t(1;2)(q21;p23)
contained a 104-kD ALK protein and the t(2;3)(p23;q21) was associated
with a 97-kD ALK protein.
Reverse transcriptase-polymerase chain reaction and fluorescence in
situ hybridization techniques have also been applied to detect the
classical t(2;5).9,20,21 Such procedures would not,
however, have provided any information on variant translocations described in the present study. In view of this, the detection of ALK
proteins using immunolabeling techniques combined with the in vitro
kinase assay would seem to constitute the easiest way to provide
evidence for novel ALK gene rearrangements in ALCL when
cytogenetic data are not available.
It has recently been proposed that ALK+ lymphomas
(`ALKomas') constitute a distinct clinicopathological
entity.17 Variant translocations involving the ALK
gene may permit the identification of new genes that could be involved
in this entity. It will be of interest to see, with increasing
experience, whether cases of ALCL with variant translocations behave
biologically and/or clinically in a different way from cases of
`ALKoma' carrying the classical t(2;5).
| |
ACKNOWLEDGMENT |
The authors thank Heike Brückner, Andrea Trumpfheller, Maria
Reichert, Sabine Roth, and Petra Stempfle for expert technical assistance.
| |
FOOTNOTES |
Submitted February 10, 1999; accepted March 22, 1999.
Supported by the Deutsche Forschungsgemeinschaft,
Sonderforschungsbereich 172, Teilprojekt C8 to G.O. and H.K.M.-H.,
and by the Leukaemia Research Fund, Grant No. 9646.
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 German Ott, MD, Pathologisches Institut der
Universität, Josef-Schneider-Str. 2, D-97080 Würzburg,
Germany.
| |
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ABSTRACT
INTRODUCTION