TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors

Brandon Lawrence, Antonio Perez-Atayde, Michele K. Hibbard, Brian P. Rubin, Paola Dal Cin, Jack L. Pinkus, Geraldine S. Pinkus, Sheng Xiao, Eunhee S. Yi, Christopher D.M. Fletcher, Jonathan A. Fletcher

Research output: Contribution to journalArticle

486 Scopus citations

Abstract

Inflammatory myofibroblastic tumors (IMTs) are neoplastic mesenchymal proliferations featuring an inflammatory infiltrate composed primarily of lymphocytes and plasma cells. The myofibroblastic cells in some IMTs contain chromosomal rearrangements involving the ALK receptor tyrosine-kinase locus region (chromosome band 2p23). ALK - which is normally restricted in its expression to neural tissues - is expressed strikingly in the IMT cells with 2p23 rearrangements. We now report a recurrent oncogenic mechanism, in IMTs, in which tropomyosin (TPM) N-terminal coiled-coil domains are fused to the ALK C-terminal kinase domain. We have cloned two ALK fusion genes, TPM4-ALK and TPM3-ALK, which encode ˜95-kd fusion oncoproteins characterized by constitutive kinase activity and tyrosylphosphorylation. Immunohistochemical and molecular correlations, in other IMTs, implicate non-TPM ALK oncoproteins that are predominantly cytoplasmic or predominantly nuclear, presumably depending on the subcellular localization of the ALK fusion partner. Notably, a TPM3-ALK oncogene was reported recently in anaplastic lymphoma, and TPM3-ALK is thereby the first known fusion oncogene that transforms, in vivo, both mesenchymal and lymphoid human cell lineages.

Original languageEnglish (US)
Article number64550
Pages (from-to)377-384
Number of pages8
JournalAmerican Journal of Pathology
Volume157
Issue number2
DOIs
StatePublished - Aug 2000

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Lawrence, B., Perez-Atayde, A., Hibbard, M. K., Rubin, B. P., Cin, P. D., Pinkus, J. L., Pinkus, G. S., Xiao, S., Yi, E. S., Fletcher, C. D. M., & Fletcher, J. A. (2000). TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. American Journal of Pathology, 157(2), 377-384. [64550]. https://doi.org/10.1016/S0002-9440(10)64550-6