A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation

Anaplastic large cell lymphomas (ALCL) are frequently associated with the t (2;5)(p23;q35), This translocation fuses the nucleophosmin (NPM) gene at 5q 35, which encodes a nucleolar protein involved in shuttling ribonucleoprote ins from the cytoplasm to the nucleus, to the anaplastic lymphoma kinase (A LK) gene at 2p23, encoding a tyrosine kinase receptor. In this report, we d escribe a typical case of ALCL whose malignant cells exhibited a novel (1;2 )(q25;p23) translocation. These cells expressed ALK protein, but, in contra st to t(2;5)-positive ALCL (which show cytoplasmic, nuclear, and nucleolar staining), labeling was restricted to the malignant cell cytoplasm. Using a polymerase chain reaction (PCR)-based technique to walk on chromosome 2 fr om the known ALK gene across the breakpoint, we showed that the gene involv ed at 1q25 is TPM3, encoding a nonmuscular tropomyosin. We subsequently ide ntified, using reverse transcription-PCR analysis of cases showing similar ALK cytoplasm-restricted staining, fusion of the ALK and TPM3 genes in 2 ot her cases of ALCL. The TPM3 gene has been previously found in papillary thy roid carcinomas as a fusion partner with the TRK kinase gene. We showed tha t TPM3 is constitutively expressed in lymphoid cell lines, suggesting that, in these t(1;2)-bearing ALCL cases, the TPM3 gene contributes an active pr omoter for ALK expression. Activation of the ALK catalytic domain probably results from homodimerization of the hybrid protein TPM3-ALK, through the T PM3 protein-protein interaction domain. The present cases of ALCL associate d with a novel t(1;2)(q25;p23) demonstrate that at least one fusion partner other than NPM can activate the intracytoplasmic domain of the ALK kinase. (C) 1999 by The American Society of Hematology.