A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma

Mirella Trinei, Luisa Lanfrancone, Elias Campo, Karen Pulford, David Y. Mason, Pier Giuseppe Pelicci, Brunangelo Falini

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Abstract

Anaplastic lymphoma kinase (ALK)-positive lymphomas ('ALKomas') constitute a distinct molecular and clinicopathological entity within the heterogeneous group of CD30-positive large cell lymphomas. In 80-85% of cases tumor cells express a M(r) 80,000 hybrid protein comprising the nucleolar phosphoprotein nucleophosmin (NPM) and the ALK. We report here the cloning and expression of a novel ALK-fusion protein from an ALK-positive lymphoma. This case was selected for molecular investigation because of (a) the absence of NPM-ALK transcripts; (b) the atypical staining patterns for ALK (cytoplasm-restricted) and for NPM (nucleus-restricted); and (c) the presence of a M(r) 96,000 ALK-protein differing in size from NPM-ALK. Nucleotide sequence analysis of ALK transcripts isolated by 5'-rapid amplification of cDNA ends revealed a chimeric mRNA corresponding to an ATIC-ALK in-frame fusion. ATIC is a bifunctional enzyme (5-aminoimidazole-4-carboxamide ribonucleotide transformylase and IMP cyclohydrolase enzymatic activities) that catalyzes the penultimate and final enzymatic activities of the purine nucleotide synthesis pathway. Expression of full-length ATIC-ALK cDNA in mouse fibroblasts revealed that the fusion protein (a) possesses constitutive tyrosine kinase activity; (b) forms stable complexes with the signaling proteins Grb2 and Shc; (c) induces tyrosine-phosphorylation of Shc; and (d) provokes oncogenic transformation. These findings point to fusion with ATIC as an alternative mechanism of ALK activation.

Original languageEnglish
Pages (from-to)793-798
Number of pages6
JournalCancer Research
Volume60
Issue number4
Publication statusPublished - Feb 15 2000

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Anaplastic Large-Cell Lymphoma
Proteins
Lymphoma
IMP cyclohydrolase
anaplastic lymphoma kinase
Hydroxymethyl and Formyl Transferases
Complementary DNA
Purine Nucleotides
Phosphoproteins
Nuclear Proteins
Protein-Tyrosine Kinases
Sequence Analysis
Tyrosine
Organism Cloning
Cytoplasm

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma. / Trinei, Mirella; Lanfrancone, Luisa; Campo, Elias; Pulford, Karen; Mason, David Y.; Pelicci, Pier Giuseppe; Falini, Brunangelo.

In: Cancer Research, Vol. 60, No. 4, 15.02.2000, p. 793-798.

Research output: Contribution to journalArticle

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