ALK is a protein, 200 kDa, a transmembrane
receptor tyrosin kinase, presumably receptor for the growth factor
pleiotrophin. In normal tissues, ALK protein is expressed only few
cells within the developing and mature nervous system (glial cells,
neurons, endothelial cells and pericytes) (11-13).
The ALK gene was discovered in the late 1980s,
when it was noted that CD30+ anaplastic large cell lymphomas (ALCLs)
may be associated with a balanced (2;5)(p23;q35) chromosomal
translocation in some cases (1-5). Subsequently, cloning of the
chromosomal breakpoints identified ALK gene, which was located at
chromosome 2p23, and NPM (encoding ubiquitously expressed
nucleophosmin), located at 5q35 (6). The resulting NPM-ALK hybrid
protein (also known as p80) contains 40% of the amino-terminal
portion of NPM linked to the entire cytoplasmic domain of ALK
The t(2;5) translocation that involves the ALK
gene accounts for about 80% of the ALCL cases (14) (Fig.
1). In the remaining cases, other variant rearrangements
involving ALK gene are seen, including t(1;2)(q21;p23),
inversion 2(p23;q35), t(2;3)(p23;q21), t(2;17)(p23;q23), and
t(X;2)(q11-12;p23). In these uncommon rearrangements ALK gene is
juxtaposed to TPM3, encoding a nonmuscle tropomyosin; TFG (TRCK
fusion gene), encoding a polypeptide with a predicted
coiled:coiled domain; ATIC, which encodes an enzyme,
transformylase/inosine monophosphate cyclohydrolase, that
participates in purine metabolism; CLTC, encoding the clathrin
heavy-chain gene; or MSN, encoding moesin, a member of the
protein 4.1 family of membrane-associated polypeptides(15-20).
ALK gene is translocated not only in ALCL, but
also in inflammatory myofibroblastic tumor. Tropomyosin 4 and
RANBP2 genes were found involved only in inflammatory
myofibroblastic tumor, nucleophosmin and TRCK fusion gene in
ALCL only, while tropomyosin 3, and clathrin heavy chain genes
were found involved in rare cases of both ALCL and inflammatory
myofibroblastic tumors (27,28). ALK has also been detected by
immunohistochemistry in some sarcomas, particularly
rhabdomyosarcoma (29). However, in most of the soft tissue
tumors, except the inflammatory myofibroblastic tumors, it
displayed merely low-level expression. It has also been
described in some cases of neuroblastoma (30).
ALK1 can also be expressed in diffuse large B cell lymphoma
(DLBCL). These are unique DLBCL with monomorphic large
immunoblast-like cells, containing large central nucleoli, which
tend to invade lymphatic sinuses. Superficially they resemble
anaplastic large cell lymphoma (ALCL) but they lack CD30. These
lymphomas express epithelial membrane antigen (as do ALCL), but
also contain cytoplasmic IgA (31). In contrast, CD30-positive
DLBCL are ALK1-negative.
ALK-positive ALCL usually present in young men,
presenting with advanced disease (stage III or IV), are commonly
associated with fever, and there is extra nodal involvement.
However, they respond well to chemotherapy and have a favourable
outcome (24,25). Interestingly, ALK-positive ALCL are
consistently BCL2-negative (26).
The main application is classification of
malignant lymphomas, viz. identification of ALCL. Furthermore
ALK is important for the identification of inflammatory
While first studies for immunohistochemical
detection used polyclonal antibodies (21,22), most studies of
ALK protein are now done with mAbs (ALK1 and ALKc). These
recognize the cytoplasmic portion of ALK and are both suitable
for immunolabeling paraffin-embedded biopsy specimens and for
Western blot analyses (11,23).
Except for the above mentioned, no tissues should be positive
for ALK by immunohistochemistry (11); a point that has important
The various translocation partners are
important for the cellular localization of the fusion protein
and therefore, important for the interpretation of the results
of immunostaining. Cytoplasmic, nuclear, and nucleolar pattern
are associated with nucleophosmin/ALK translocation, membranous
and diffuse cytoplasmic with tropomyosin 3/ALK, diffuse
cytoplasmic with TRCK fusion gene/ALK and ATIC/ALK
translocations, punctuate cytoplasmic with clathrin heavy
chain/ALK translocation, and nuclear membrane staining with
RANBP2/ALK. All of these translocations result in dimerization
of the N-terminal segment of ALK protein and its constitutive
activation, which appears to be oncogenic. The dimerization of
the N-terminal segment of ALK occurs as a result of these
translocations because all of the fusion partners share the
capacity for self-association.
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