Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis.
The non-Hodgkin lymphoma (NHL) subtype anaplastic large-cell lymphoma (ALCL) is frequently associated with a t(2;5)(p23;q35) that results in the fusion of the ubiquitously expressed nucleophosmin (NPM) gene at 5q35 to the anaplastic lymphoma kinase (ALK) gene at 2p23, which is not normally expressed in hematopoietic tissues. Approximately 20% of ALCLs that express ALK do not contain the t(2;5), suggesting that other genetic abnormalities can result in aberrant ALK expression. Here we report the molecular characterization of an alternative genetic means of ALK activation, the inv(2)(p23q35). This recurrent abnormality produces a fusion of the amino-terminus of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a bifunctional homodimeric enzyme that catalyzes the penultimate and final steps of de novo purine nucleotide biosynthesis, with the intracellular portion of the ALK receptor tyrosine kinase. RT-PCR analysis of 5 ALCL tumors that contained the inv(2) revealed identical ATIC-ALK fusion cDNA junctions in all of the cases. Transient expression studies show that the ATIC-ALK fusion transcript directs the synthesis of an approximately 87-kd chimeric protein that is localized to the cytoplasm, in contrast to NPM-ALK, which typically exhibits a cytoplasmic and nuclear subcellular distribution. ATIC-ALK was constitutively tyrosine phosphorylated and could convert the IL-3-dependent murine hematopoietic cell line BaF3 to cytokine-independent growth. Our studies demonstrate an alternative mechanism for ALK involvement in the genesis of NHL and suggest that ATIC-ALK activation results from ATIC-mediated homodimerization. In addition, expected decreases in ATIC enzymatic function in ATIC-ALK-containing lymphomas may render these tumors more sensitive to antifolate drugs such as methotrexate. (Blood. 2000;95:2144-2149)
Ma
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Department of Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, University of Tennessee, College of Medicine, Memphis, TN 38105-2794, USA.
Cools
J
J
Marynen
P
P
Cui
X
X
Siebert
R
R
Gesk
S
S
Schlegelberger
B
B
Peeters
B
B
De Wolf-Peeters
C
C
Wlodarska
I
I
Morris
S W
SW
D000293:Adolescent; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002460:Cell Line; D007446:Chromosome Inversion; D002889:Chromosomes, Human, Pair 2; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000096:biosynthesis*; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009097:Multienzyme Complexes / Q000096:biosynthesis*; D009709:Nucleotide Deaminases / Q000096:biosynthesis*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism*; D011687:Purines / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection
D009097:Multienzyme Complexes; D015514:Oncogene Proteins, Fusion; D011687:Purines; C113120:inosine monophosphate synthase; D019877:Hydroxymethyl and Formyl Transferases; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D009709:Nucleotide Deaminases