A New Fusion Gene TPM3-ALK in Anaplastic Large Cell Lymphoma Created by a (1;2)(q25;p23) Translocation

• Published in: Blood 1999-05, Vol.93 (9), p.3088-3095
• Main Authors: Lamant, Laurence, Dastugue, Nicole, Pulford, Karen, Delsol, Georges, Mariamé, Bernard
• Format: Article
• Language: English
• Subjects: Anaplastic Lymphoma Kinase; Base Sequence; Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 2; DNA Primers; Hematologic and hematopoietic diseases; Humans; Karyotyping; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Large-Cell, Anaplastic - genetics; Lymphoma, Large-Cell, Anaplastic - pathology; Medical sciences; Molecular Sequence Data; Oncogene Proteins, Fusion - genetics; Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Translocation, Genetic; Tropomyosin - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V93.9.3088

Anaplastic large cell lymphomas (ALCL) are frequently associated with the t(2;5)(p23;q35). This translocation fuses the nucleophosmin (NPM) gene at 5q35, which encodes a nucleolar protein involved in shuttling ribonucleoproteins from the cytoplasm to the nucleus, to the anaplastic lymphoma kinase (ALK) gene at 2p23, encoding a tyrosine kinase receptor. In this report, we describe a typical case of ALCL whose malignant cells exhibited a novel (1;2)(q25;p23) translocation. These cells expressed ALK protein, but, in contrast 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 from the known ALK gene across the breakpoint, we showed that the gene involved at 1q25 is TPM3, encoding a nonmuscular tropomyosin. We subsequently identified, using reverse transcription-PCR analysis of cases showing similar ALK cytoplasm-restricted staining, fusion of the ALK andTPM3 genes in 2 other cases of ALCL. The TPM3 gene has been previously found in papillary thyroid carcinomas as a fusion partner with the TRK kinase gene. We showed that TPM3 is constitutively expressed in lymphoid cell lines, suggesting that, in these t(1;2)-bearing ALCL cases, the TPM3 gene contributes an active promoter for ALK expression. Activation of the ALK catalytic domain probably results from homodimerization of the hybrid protein TPM3-ALK, through the TPM3 protein-protein interaction domain. The present cases of ALCL associated 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.