Abstract
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase involved in neuronal and gut development. Initially discovered in T cell lymphoma, ALK is frequently affected in diverse cancers by oncogenic translocations. These translocations involve different fusion partners that facilitate multimerisation and autophosphorylation of ALK, resulting in a constitutively active tyrosine kinase with oncogenic potential. ALK fusion proteins are involved in diverse cellular signalling pathways, such as Ras/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Janus protein tyrosine kinase (JAK)/STAT. Furthermore, ALK is implicated in epigenetic regulation, including DNA methylation and miRNA expression, and an interaction with nuclear proteins has been described. Through these mechanisms, ALK fusion proteins enable a transcriptional programme that drives the pathogenesis of a range of ALK-related malignancies.
Highlights
Anaplastic lymphoma kinase (ALK) was first successfully cloned in 1994 when it was reported in the context of a fusion protein in cases of anaplastic large cell lymphoma (ALCL) [1]
Examples include: prostate cancer-associated transcript 1 (PCAT-1), which promotes proliferation and is a target of polycomb repressive complex 2 (PRC2), whose regulation has been linked with prostate cancer [83]; antisense non-coding RNA in the INK4 Locus (ANRIL) which represses the tumour suppressors p16INK4A and INK4b/p15INK4B, and which is upregulated in prostate cancer [84]; and HOX antisense intergenic RNA (HOTAIR), whose overexpression is associated with poor prognosis in breast, liver, colorectal, gastrointestinal and pancreatic cancers, and has been proposed to increase tumour invasiveness and metastasis [85]
Nucleophosmin 1 (NPM1)-ALK is well described in driving expression of both basic leucine zipper and basic helix-loop-helix (HLH) transcription factors [80,81,86,87,88]. bZIP transcription factors are characterised by a conserved bZIP region which enables DNA binding and include the AP1 complexes which have been extensively characterised in ALK+ ALCL [80]
Summary
Anaplastic lymphoma kinase (ALK) was first successfully cloned in 1994 when it was reported in the context of a fusion protein in cases of anaplastic large cell lymphoma (ALCL) [1]. It was subsequently characterised as a membrane-bound tyrosine kinase expressed during neonatal development of the nervous system more is known about its roles in disease rather than its normal physiological functions [2]. Through the course of this review, these means shall be discussed with an emphasis placed on how Nucleophosmin 1 (NPM1)-ALK (the most studied ALK-fusion protein) mediates oncogenesis through transcriptional regulation.
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