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Review
. 2011 Oct;21(4):267-75.
doi: 10.1016/j.semcancer.2011.09.005. Epub 2011 Sep 16.

Emerging importance of ALK in neuroblastoma

Affiliations
Review

Emerging importance of ALK in neuroblastoma

Anna M Azarova et al. Semin Cancer Biol. 2011 Oct.

Abstract

Since the original descriptions of gain-of function mutations in anaplastic lymphoma kinase (ALK), interest in the role of this receptor tyrosine kinase in neuroblastoma development and as a potential therapeutic target has escalated. As a group, the activating point mutations in full-length ALK, found in approximately 8% of all neuroblastoma tumors, are distributed evenly across different clinical stages. However, the most frequent somatic mutation, F1174L, is associated with amplification of the MYCN oncogene. This combination of features appears to confer a worse prognosis than MYCN amplification alone, suggesting a cooperative effect on neuroblastoma formation by these two proteins. Indeed, F1174L has shown more potent transforming activity in vivo than the second most common activating mutation, R1275Q, and is responsible for innate and acquired resistance to crizotinib, a clinically relevant ALK inhibitor that will soon be commercially available. These advances cast ALK as a bona fide oncoprotein in neuroblastoma and emphasize the need to understand ALK-mediated signaling in this tumor. This review addresses many of the current issues surrounding the role of ALK in normal development and neuroblastoma pathogenesis, and discusses the prospects for clinically effective targeted treatments based on ALK inhibition.

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Conflict of interest statement

Conflict of interests None

Figures

Figure 1
Figure 1. Domain structure of ALK
The N-terminal, extracellular region of human ALK contains a signal peptide (aa 1-26), two MAM domains (aa 264-427 and 480-626), one LDL domain (aa 453-471) and a glycine-rich domain (aa 816–940). The transmembrane domain (TM) (aa 1030-1058) connects the extracellular and intracellular domains. The intracellular (cytoplasmic) domain contains the juxtamembrane (1058-1122) and the tyrosine kinase catalytic domains (aa 1122-1376).(SigP, signal peptide; TM, transmembrane) , not drawn to scale.
Figure 2
Figure 2. Signaling by ALK
ALK signaling can be activated by ligand binding (blue arrows), gene amplification or mutation. The receptor is then auto-phosphorylated, stimulating signal transduction through the indicated downstream pathways.

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