Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma.

Abstract:

:Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short-form ALK protein (ALK(del2-3)) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALK(del2-3) was autophosphorylated in NB-1 cells as well as in ALK(del2-3)-transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALK(del2-3)-transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi-mediated ALK knockdown resulted in the growth suppression of ALK(del2-3)-expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis.

journal_name

Oncogene

journal_title

Oncogene

authors

Okubo J,Takita J,Chen Y,Oki K,Nishimura R,Kato M,Sanada M,Hiwatari M,Hayashi Y,Igarashi T,Ogawa S

doi

10.1038/onc.2011.616

subject

Has Abstract

pub_date

2012-11-01 00:00:00

pages

4667-76

issue

44

eissn

0950-9232

issn

1476-5594

pii

onc2011616

journal_volume

31

pub_type

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