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

Abstract

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.

Anaplastic large cell lymphoma in paediatric and young adult patients

“…The most frequent variant translocation is the t(1;2)(q25;p23), found in 15% to 18% of ALK+ ALCLs (Lamant et al , ). In theses cases, which express the TPM3‐ALK protein, ALK staining is restricted to the cytoplasm of malignant cells and in virtually all cases there is stronger staining on the cell membrane.…”

RET and NTRK1 proto‐oncogenes in human diseases

“…Very recently, two fusion partner genes of NTRK1, TFG and TPM3, were reported to fuse to ALK in anaplastic large cell lymphoma (Lamant et al, 1999; Hernandez et al, 2002). It has been demonstrated that three different variants of TFG‐ALK involving different breakpoints in TFG gene, have in vitro transforming potential and bind to signal transduction pathway proteins such as Grb2, Shc, and PLCγ (Hernandez et al, 2002).…”

Molecular genetics of childhood, adolescent and young adult non‐Hodgkin lymphoma

“…Different ALK translocations can also be seen in ALK + ALCL and presumably employ similar mechanisms. Other ALK fusion partners in paediatric ALCL include TPM3 at 1q25 (Lamant et al , ), TFG at 3q21 (Hernandez et al , ), ATIC due to cryptic inversions in chromosome 2 (p23q35) (Colleoni et al , ; Trinei et al , ), CLTC at 17q23 (Touriol et al , ; Cools et al , ), MSN at Xq11‐12 (Tort et al , ), TRAF1 at 9q32 (Abate et al , ) and MYH9 at 22q11·2 (Lamant et al , ). Also, ALK fusions are not unique to ALCL, as these translocations or others occur in neoplasms, such as DLBCL, inflammatory myofibroblastic tumour, colon and breast cancer, renal cell and esophageal squamous cell carcinoma, plasmacytoma and non‐small‐cell lung cancer (Boi et al , ).…”