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

Inflammatory myofibroblastic tumors (IMTs) are neoplastic mesenchymal proli ferations featuring an inflammatory infiltrate composed primarily of lympho cytes and plasma cells. The myofibroblastic cells in some IMTs contain chro mosomal rearrangements involving the ALK receptor tyrosine-kinase locus reg ion (chromosome band 2p23). ALK-which is normally restricted in its express ion to neural tissues-is expressed strikingly in the IMT cells with 2p23 re arrangements. We now report a recurrent oncogenic mechanism, in IMTs, in wh ich 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 similar to 95-kd fusion oncoproteins characterized by constitutive kinase activity and tyrosylphosphorylation. Immunohistochem ical and molecular correlations, in other IMTs, implicate non-TPM ALK oncop roteins that are predominantly cytoplasmic or predominantly nuclear, presum ably depending on the subcellular localization of the ALK fusion partner. N otably, a TPM3-ALK oncogene was reported recently in anaplastic lymphoma, a nd TPM3-ALK is thereby the first known fusion oncogene that transforms, in vivo, both mesenchymal and lymphoid human cell lineages.