Wlodarska_subbed.qxp 11/8/09 10:34 am Page 51
Oncogenic Anaplastic Lymphoma Kinase Rearrangements in Lymphoma
diagnosis of ALK
+
tumours (see Figure 2). Additional diagnostic Figure 1: Schematic Diagrams of the Known Anaplastic
techniques include conventional cytogenetics, fluorescence in situ
Lymphoma Kinase Fusion Proteins in Lymphoma
hybridisation (FISH) (see Figure 3) and molecular analysis.
1,058
1,620
Anaplastic Lymphoma Kinase-positive
ALK TK
Large B-cell Lymphoma
Extracellular domain Cytoplasmic domain
117 680
Subsequent studies showed that ALK expression is not restricted to
NPM1-ALK TK
ALCL but also hallmarks other tumours, including large B-cell
229 792
lymphoma (LBCL). The first series of ALK-expressing LBCL was reported
ATIC-ALK TK
by Delsol et al.
22
in 1997. To date, 54 ALK
+
LBCL cases have
221 784
been described.
23–25
The recent WHO classification of haematolymphoid
TPM3-ALK
TK
neoplasms considers ALK
+
LBCL a distinct lymphoma entity.
8
240 803
Cytologically, the lymphoma cells display either an immunoblastic or a
TFG
XL
-ALK
TK
plasmablastic morphology; occasional binucleated or multinucleated
193 756
cells mimicking Hodgkin and Reed-Sternberg (H/RS) cells may also be
TFG
L
-ALK
TK
seen.
26
ALK
+
LBCL shows a distinct immunophenotype, characterised by
138 701
the strong expression of ALK and EMA and expression of plasma cell
TFG
S
-ALK
TK
markers such as CD138/VS38 and MUM1. Notably, the neoplastic cells
1,634 2,197
have lost expression of B-cell-lineage-associated leukocyte antigens
CLTC-ALK TK
such as CD19, CD20 and CD79a, suggesting terminal plasma cell
differentiation.
22,23
The disease spans all age groups (nine to 72 years of
1,172 1,735
ALO17-ALK TK
age, with a median age of 38 years), but approximately 22% of the cases
occurred in the paediatric population (<18 years of age). The lymphoma
448 1,005
is more common in men than women (M:F ratio of 3:1).
23
Most patients
MSN-ALK TK
with ALK
+
LBCL presented with stage III/IV disease and their clinical 1,645 2,201
outcome was worse than ALK
+
ALCL, particularly in the paediatric
MYH9-ALK TK
population. Despite aggressive treatment, approximately half of the
989 1,552
patients died of disease three to 33 months after therapy. No difference
SEC31A-ALK TK
in survival between paediatric and adult cases was found, despite more
With the exception of MSN-anaplastic lymphoma kinase (ALK) and MYH9-ALK, the ALK
intensive therapies in the paediatric population.
23
portion present in the fusions is identical, comprising the final 563 cytoplasmic amino acid
residues of ALK. MSN-ALK and MYH9-ALK contain the terminal 557 and 556 ALK amino
acid residues, respectively. The numbers correspond to the number of amino acid residues
Similar to ALK
+
ALCL, the aberrant ALK expression in ALK
+
LBCL is also
of the partner protein present in the fusion, and the total number of amino acids included in
driven by 2p23/ALK translocations, of which t(2;17)(p23;q23) is the
each fusion protein. The normal ALK protein is shown at the top and consists of a large
extracellular domain, a 27-amino-acid transmembrane domain (dark grey box) and a
most frequent (65%). This aberration leads to a chimaeric CLTC-ALK
cytoplasmic domain containing a tyrosine kinase (TK) catalytic domain. The breakpoint mostly
protein and manifests as a distinctive granular cytoplasmic
occurs at amino acid 1,058, designated by the arrow, immediately after the transmembrane
domain, leaving the cytoplasmic domain and the tyrosine kinase catalytic domain intact. The
expression of ALK
27–35
(see Table 1 and Figure 3). Interestingly, only a
light-grey boxes are putative oligomerisation domains, i.e. nucleoplasmin domain (NPM1),
few ALK
+
LBCL cases (13%) showed the t(2;5)(p23;q35)/NPM1-ALK
dimerisation domain (ATIC), coiled coils (TPM3, TFG, MSN, ALO17 and MYH9), multimerisation
domain (CLTC) and WD40-like repeats (SEC31A).
rearrangement, commonly occurring in ALK
+
ALCL
25,36–38
(see Table 1).
Recently, we have identified a new cryptic SEC31A-ALK fusion in an
ALK
+
LBCL case generated by complex rearrangements targeting the expression of full-length ALK messenger RNA (mRNA) and/or protein
respective loci at 4q21 and 2p23.
25
A functional analysis of the has been described in a variety of primary tumours and cancer cell
SEC31A-ALK protein and its downstream effectors revealed that this lines including glioblastoma,
76,77
rhabdomyosarcoma,
78
Ewing sarcoma
fusion is a constitutively activated tyrosine kinase responding in vitro and retinoblastoma
76
and breast cancer.
79
Additional studies are
to the ALK inhibitor NVP-TAE-684. required to assess the possible role of full-length ALK and ALK fusion
forms in the pathogenesis and progression of these non-
Anaplastic Lymphoma Kinase Rearrangements haematopoietic tumours.
in Non-haematological Malignancies
Apart from ALK
+
ALCL and LBCL, various tumours of mesenchymal and Mechanism of Anaplastic Lymphoma
epithelial origin, including inflammatory myofibroblastic tumour Kinase Fusion Kinase Activation
(IMT),
39–41
lung cancer
42–53
and oesophageal squamous cell carcinoma Under normal conditions, activation of RTKs such as ALK depends on
(SCC),
54,55
were found to implicate the ALK gene and inappropriately ligand binding. Two putative ALK ligands have been proposed,
express the ALK protein (see Table 1). Particularly interesting is the pleiotrophin (PTN) and midkine (MK),
80,81
which show similar expression
finding of the same translocations and/or ALK fusions in ALK
+
patterns to ALK (high levels during neural development and decreased
malignancies of different origin (see Table 1). TPM3-ALK,
56–59
ATIC-ALK,
60
expression following birth),
82–85
indicating that PTN, MK and ALK could be
CLTC-ALK
59,61,62
and SEC31A-ALK
63
were reported in lymphomas and IMT, important for normal neural function. Stoica and co-workers showed
and TPM4-ALK has been found in IMT and SCC.
57,59,64
So far, CARS-ALK
65,66
that PTN-induced mitogenesis resulted in increased phosphorylation of
and RANBP2-ALK
62,67,68
have only been found in IMT, and EML4-ALK and ALK substrates in ALK-transfected cells,
80
and that MK binds to ALK-
KIF5B-ALK in non-small-cell lung carcinoma (see Table 1).
42–53
Recently, transfected 32Dcl3 cells.
81
Furthermore, ALK is likely to be involved in
oncogenic mutations of the ALK kinase and amplification of ALK have PTN-stimulated phosphorylation and activation of PI3K, MAPK and
been discovered in neuroblastoma tumours.
69–75
In addition, deregulated PKB/AKT anti-apoptotic proteins.
77,86
EUROPEAN HAEMATOLOGY 51
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