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 fusio n of the ubiquitously expressed nucleophosmin (NPM) gene at 5q35 to the ana plastic lymphoma kinase (ALK) gene at 2p23, which Is not normally expressed in hematopoietic tissues. Approximately 20% of ALCLs that express ALK do n ot contain the t(2;5), suggesting that other genetic abnormalities can resu lt in aberrant ALK expression. Here we report the molecular characterizatio n of an alternative genetic means of ALK activation, the inv(2)(p23q35), Th is recurrent abnormality produces a fusion of the amino-terminus of 5-amino imidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a bifunctional homodimeric enzyme that catalyzes the penultimate a nd final steps of de novo purine nucleotide biosynthesis, with the intracel lular portion of the ALK receptor tyrosine kinase, RT-PCR analysis of 5 ALC L tumors that contained the inv(a) revealed identical ATIC-ALK fusion cDNA junctions in all of the cases. Transient expression studies show that the A TIC-ALK fusion transcript directs the synthesis of an approximately 87-kd c himeric protein that is localized to the cytoplasm, in contrast to NPM-ALK, which typically exhibits a cytoplasmic and nuclear sub-cellular distributi on. ATIC-ALK was constitutively tyrosine phosphorylated and could convert t he IL-3-dependent murine hematopoietic call line BaF3 to cytokine-independe nt growth, Our studies demonstrate an alternative mechanism for ALK involve ment in the genesis of NHL and suggest that ATIC-ALK activation results fro m ATIC-medlated homodimerization, In addition, expected decreases in ATIC e nzymatic function in ATIC-ALK-containing lymphomas may render these tumors more sensitive to antifolate drugs such as methotrexate. (C) 2000 by The Am erican Society of Hematology.