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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2144-2149
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
Zhigui Ma,
Jan Cools,
Peter Marynen,
Xiaoli Cui,
Reiner Siebert,
Stefan Gesk,
Brigitte Schlegelberger,
Benjamin Peeters,
Christiane De Wolf-Peeters,
Iwona Wlodarska, and
Stephan W. Morris
From the Department of Pathology and Laboratory Medicine, St. Jude
Children's Research Hospital, and the Department of Pediatrics,
University of Tennessee, College of Medicine, Memphis, TN; the Center
for Human Genetics and Flanders Interuniversity Institute of
Biotechnology, and the Department of Pathology, University of Leuven,
Leuven, Belgium; and the Department of Human Genetics, University of
Kiel, Kiel, Germany.
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.
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