The Anaplastic Lymphoma Kinase in the Pathogenesis of Cancer

Roberto Chiarle; *‡ Claudia Voena; *‡ Chiara Ambrogio; *‡ Roberto Piva; *‡§ Giorgio Inghirami*‡§

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In This Article

Abstract and Introduction

Tyrosine kinases are involved in the pathogenesis of most cancers. However, few tyrosine kinases have been shown to have a well-defined pathogenetic role in lymphomas. The anaplastic lymphoma kinase (ALK) is the oncogene of most anaplastic large cell lymphomas (ALCL), driving transformation through many molecular mechanisms. In this Review, we will analyse how translocations or deregulated expression of ALK contribute to oncogenesis and how recent genetic or pharmacological tools, aimed at neutralizing its activity, can represent the basis for the design of powerful combination therapies.

It is now agreed that anaplastic large cell lymphoma (ALCL) is a distinct subset of T-cell non-Hodgkin lymphomas (NHL)[1] for which a normal cellular counterpart has not yet been established. Morphological, immunophenotypical and molecular genetic studies have elucidated many of the pathogenetic events in the development and progression of ALCL. Prior to the discovery of the CD30 antigen (also known as tumour necrosis factor receptor superfamily, member 8 (TNFRSF8)) as a characteristic marker,[1] ALCL was variously misinterpreted as different diseases: histiocytic lymphoma, malignant histiocytosis, Hodgkin disease, malignant melanoma, metastatic carcinoma or malignant fibrous histiocytoma.[3] The lymphoid origin was finally determined from the presence of clonal T-cell receptor (TCR) gene rearrangements and/or the expression of T-cell lineage-associated antigens. Primary systemic ALCL has a peak incidence in childhood, accounting for approximately 40% of NHL cases diagnosed in paediatric patients,[4] whereas it accounts for <5% of NHL in adults,[5] and it is seen mostly in males. Patients present with stage III to IV disease, often with multiple extranodal sites of involvement.[6,7]

In the late 1980s, the t(2;5)(p23;q35) translocation was described by several groups as the most frequent in ALCL[8,9,10] and in 1994 the product of this translocation was identified as the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) fused to nucleophosmin (NPM1, also known as NPM and B23)[11] (Timeline). Many groups have since discovered additional translocations in which ALK is fused to other partners ( Table 1 ). Nevertheless, ~15–40% of ALCL[1,3,12] do not express ALK or other recurrent translocations. Although the current World Health Organization classification of lymphomas considers ALK-positive and ALK-negative ALCL to share the same category, it is now suggested that these two types of lymphomas, as well as cutaneous ALCL, might correspond to different entities[12] (European Association for Haematopathology).

This Review illustrates the translocations involving ALK and the molecular mechanisms that underlie the pathogenesis of ALK-positive ALCL. We will also discuss the potential of ALK as a specific target for the therapy of ALCL and other cancers.

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