The subset of CD30-positive anaplastic large cell lymphomas (ALCL) with the NPM-ALK gene fusion arising from the t(2;5)(p23;q35) forms a distinct clinical and prognostic entity. Recently, various cytogenetic, molecular, and protein studies have provided evidence for the existence of several types of variant ALK fusions in up to 20% of ALK؉ ALCL, of which only one, a TPM3-ALK fusion resulting from a t(1;2)(q25;p23), has so far been cloned. A cryptic inv(2)(p23q35) has been described as another recurrent cytogenetic alteration involving ALK and an unidentified fusion partner in some ALCL. In a screen for variant ALK gene fusions, we identified two ALCL that were negative for NPM-ALK by reverse transcriptase-polymerase chain reaction, but were positive for cytoplasmic ALK with both polyclonal and monoclonal antibodies to the ALK tyrosine kinase domain, consistent with ALK deregulation by an alteration other than the t(2;5) Case 1 was a T-lineage nodal and cutaneous ALCL in a 52-year-old woman, and Case 2 was a Tlineage nodal ALCL in a 12-year-old girl. FISH analysis confirmed ALK rearrangement in both cases. An inverse polymerase chain reaction approach was then used to identify the ALK translocation partner in Case 1. We found an in-frame fusion of ALK to ATIC, a gene previously mapped to 2q34-q35. We then confirmed by DNA polymerase chain reaction the localization of ATIC to yeast artificial chromosome ( Anaplastic large cell lymphoma (ALCL) is recognized as a distinct subtype of non-Hodgkin's lymphoma (NHL) in recent lymphoma classifications. This disease constitutes approximately 5% of all NHL but accounts for 30 to 40% of pediatric large cell lymphomas.1 ALCL expresses Ki-1 (CD30), an antigen originally detected on Reed-Sternberg cells of Hodgkin's disease, later shown to be a member of tumor necrosis factor receptor family. 2,3 In its classical or common form, ALCL shows an often bizarre, anaplastic morphology with sinusoidal infiltration of lymph nodes and a pseudocohesive appearance, and T or null phenotype. 4 The status of ALCL as a discrete entity had long been controversial, 5,6 and its recent separation into at least two subsets (see Discussion) stems from cytogenetic and molecular studies of the translocation seen in about 40 to 60% of cases, t(2;5)(p23;q35). [7][8][9] In 1994, the t(2;5) was found to involve a novel gene at 2p23 encoding a tyrosine kinase, ALK (anaplastic lymphoma kinase), and the NPM (nucleophosmin) gene at