A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma.
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 Mr 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 Mr 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.
Trinei
M
M
Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy.
Lanfrancone
L
L
Campo
E
E
Pulford
K
K
Mason
D Y
DY
Pelicci
P G
PG
Falini
B
B
D016475:3T3 Cells; D000293:Adolescent; D000595:Amino Acid Sequence; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D003001:Cloning, Molecular; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry* / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000032:analysis; D000090243:Nucleophosmin; D009709:Nucleotide Deaminases / Q000032:analysis*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000032:analysis*; D020794:Receptor Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins / Q000032:analysis*
C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D000090243:Nucleophosmin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D009709:Nucleotide Deaminases; C021436:IMP cyclohydrolase