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Haematological Malignancies
Oncogenic Anaplastic Lymphoma Kinase Rearrangements in Lymphoma
Katrien Van Roosbroeck
1
and Iwona Wlodarska
2
1. PhD Student; 2. Staff Member, Centre for Human Genetics, University Hospital of Gasthuisberg, Catholic University of Leuven
Abstract
Lymphomas expressing anaplastic lymphoma kinase (ALK) represent two distinct lymphoma entities: ALK-positive T-/null-cell anaplastic
large cell lymphoma (ALK
+
ALCL) and ALK-positive large B-cell lymphoma (ALK
+
LBCL). In both subtypes, the inappropriate expression of
ALK is driven by 2p23/ALK-involving chromosomal translocations found to target several partner genes. These translocations lead to
constitutively activated and oncogenic ALK fusions, of which nucleophosmin (NPM1)-ALK associated with t(2;5)(p23;q35) is the most
common. Recently, various ALK fusions, including those previously described in lymphomas, have been identified in several types of non-
haematological malignancy. Identification of further types of ALK
+
tumours is clinically important because in future these patients may
benefit from targeted therapy, already applied in neoplasms driven by, for example, the mutated ABL1, KIT and PDGFRA/B tyrosine kinases.
In this article, we will focus mainly on oncogenic ALK rearrangements in lymphomas and their molecular consequences.
Keywords
Oncogene, anaplastic lymphoma kinase, anaplastic large cell lymphoma, large B-cell lymphoma
Disclosure: The authors have no conflicts of interest to declare.
Received: 21 May 2009 Accepted: 16 July 2009
Correspondence: Iwona Wlodarska, Centre for Human Genetics, KU Leuven, Gasthuisberg, Herestraat 49, Box 602, B-3000 Leuven, Belgium.
E:
Iwona.Wlodarska@uz.kuleuven.ac.be
Anaplastic Lymphoma Kinase common type, composed of atypical large, pleomorphic cells with an
Located at 2p23, the anaplastic lymphoma kinase (ALK) gene codes for abundant cytoplasm, is seen in approximately 80% of cases, and
a receptor tyrosine kinase (RTK). This gene was initially identified in the morphological variants, including lymphohistiocytic, small- and giant-
chimeric nucleophosmin (NPM)-ALK fusion driven by the t(2;5)(p23;q35), cell types, are observed in the remaining cases.
9,10
ALK
+
ALCL cases
a recurrent translocation in anaplastic large cell lymphoma (ALCL).
1
The exhibit a cytotoxic T-cell or null (i.e. lacking expression of both T- and
ALK gene contains 6,226bp and encodes a 177kDa protein that is B-cell markers) phenotype and frequently express epithelial
transformed to a mature ALK RTK of approximately 200kDa by post- membrane antigen (EMA) and CD30. The disease tends to occur in the
translational modifications such as N-glycosylation.
2
In common with first three decades of life, with mean age at onset <30 years, and
other RTKs, ALK consists of a large extracellular ligand-binding domain, shows a slight male predominance (male to female [M:F] ratio of
a lipophilic transmembrane-spanning segment and a cytoplasmic 1.5–1).
4,6–18
Although ALK
+
ALCLs are highly aggressive, patients with
tyrosine kinase catalytic region (see Figure 1). Due to the significant this lymphoma have a more favourable prognosis compared with ALK-
homology of the extracellular domain to leukocyte tyrosine kinase (LTK), negative ALCL (ALK
-
ALCL) patients; the overall five-year survival rate
ALK is classified in the insulin-receptor superfamily of RTKs; the function approaches 80% in ALK
+
ALCL and 48% in ALK
-
ALCL.
4,8,15,17
Multivariate
of the ALK receptor is still poorly characterised. Expression of ALK in analysis has shown that good prognosis of patients with ALK
+
ALCL
normal tissues is restricted to rare scattered neural cells, pericytes and strongly correlates with expression of ALK, but not with younger age
endothelial cells in the brain.
1–3
Recent data suggest that ALK plays a role and/or presence in low international prognostic index risk groups.
4,15
in embryonic neural development and differentiation.
4,5
The inappropriate expression of ALK in ALK
+
ALCL derives from
chromosomal translocations targeting the 2p23/ALK locus. Occurring
Anaplastic Lymphoma Kinase in 84% of ALK
+
ALCL, the most frequent, t(2;5)(p23;q35), results in the
Rearrangements in Lymphoma fusion of the amino-terminal end of NPM (currently designated as
Anaplastic Lymphoma Kinase-positive NPM1) with the intracytoplasmic portion of ALK.
1,8,19,20
Variant
Anaplastic Large Cell Lymphoma translocations, seen in the remaining ALK
+
ALCL cases, target several
ALK
+
ALCL (informally ALKoma) accounts for approximately 60–80% of partner genes including TPM3/1q21, ATIC/2q35, TFG/3q12,
all ALCL cases.
4,6,7
In the World Health Organization (WHO) classification CLTC/17q23, ALO17/17q25, MYH9/22q12, MSN/Xq11 and SEC31A/4q21
of haematolymphoid neoplasms, ALK
+
ALCL is recognised as a (see Table 1). Four fusions, TFG-ALK, MSN-ALK, ALO17-ALK and MYH9-
separate entity among mature T-cell lymphomas.
8
These tumours form ALK, have been exclusively observed in ALK
+
ALCL
21
(see Table 1).
a homogenous group in terms of the immunophenotype and clinical Given that normal lymphoid cells do not express the ALK protein,
behaviour, but demonstrate a heterogeneous morphology. The immunostaining with ALK-specific antibodies is routinely used for the
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