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,* and Jonathan A. Fletcher* § From the Department of Pathology,* Brigham and Women’s Hospital, Boston, Massachusetts; the Department of Pathology, † Children’s Hospital Boston, Massachusetts; and the Department of Pediatric Oncology, § Dana-Farber Cancer Institute, Boston, Massachusetts; and the Department of Pathology, ‡ University of California, San Diego Medical Center, San Diego, California Inflammatory myofibroblastic tumors (IMTs) are neo- plastic mesenchymal proliferations featuring an in- flammatory infiltrate composed primarily of lympho- cytes and plasma cells. The myofibroblastic cells in some IMTs contain chromosomal rearrangements in- volving the ALK receptor tyrosine-kinase locus region (chromosome band 2p23). ALK—which is normally restricted in its expression to neural tissues—is ex- pressed strikingly in the IMT cells with 2p23 rear- rangements. 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 en- code 95-kd fusion oncoproteins characterized by constitutive kinase activity and tyrosylphosphoryla- tion. Immunohistochemical and molecular correla- tions, in other IMTs, implicate non-TPM ALK onco- proteins that are predominantly cytoplasmic or pre- dominantly 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. (Am J Pathol 2000, 157:377–384) The inflammatory myofibroblastic tumor (IMT) 1–4 is a clinicopathologically distinctive but biologically contro- versial entity that was defined originally as a nonneoplas- tic lesion. IMTs arise usually in the soft tissues, most often in the abdomen of children and adolescents, and they are composed of myofibroblastic spindle cells admixed with a prominent inflammatory infiltrate of lymphocytes, plasma cells, and, less often, acute inflammatory cells. Notably, many patients with IMTs present with constitu- tional symptoms of fever and weight loss, and these same patients are often anemic and thrombocythemic. However, it is unclear whether the constitutional symp- toms and inflammatory infiltrate are induced by tumor-cell factors or, alternately, whether the constitutional symp- toms are secondary to the inflammatory process. The uncertain pathogenesis of IMTs, and the ongoing question of its neoplastic versus reactive nature, is re- flected in the large number of names which have been bestowed on this disorder. IMTs arising in the lung, par- ticularly those that are well circumscribed, are generally cured by surgical excision. Until recently, these were referred to as “plasma cell granulomas,” “inflammatory pseudotumors,” or “pseudosarcomatous myofibroblastic proliferations.” Intra-abdominal IMTs may pursue a some- what more aggressive clinical course with multiple recur- rences and with potential for metastatic spread in rare cases. Such tumors have often been referred to as “in- flammatory myofibroblastic tumor” or “inflammatory fibro- sarcoma.” 1,2 However, most IMTs have overlapping his- tological characteristics and it is difficult to distinguish those with neoplastic potential from the potentially reac- tive subset that belong under the umbrella category of “inflammatory pseudotumor.” Another complicating fea- ture, with respect to classification, is that differences in clinical behavior, between different IMT subcategories, do not exclude a common pathogenesis. Cytogenetic banding studies were the first assays to demonstrate unequivocal clonal mutations—indicative of a neoplastic pathogenesis—in IMTs. 5–10 Approximately 50% of soft-tissue IMT karyotypes contain clonal rear- rangements of the chromosome 2 short arm, 5–10 and each of two cytogenetically characterized IMTs arising in bone contained rearrangements of the HMGIC region on chromosome band 12q15. 8 Recently, Griffin et al 10 showed that IMT 2p rearrangements fall within an 100-kb region containing the ALK receptor tyrosine- kinase locus, on chromosome band 2p23. These rear- rangements were associated with striking ALK expres- sion in the IMT myofibroblastic spindle cells. 10 ALK is a Accepted for publication May 4, 2000. The sequences reported in this paper have been deposited in the GenBank database (accession nos. AF186109 and AF186110). Address reprint requests to Jonathan A. Fletcher, M.D., Department of Pathology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. E-mail: jfletcher@rics.bwh.harvard.edu. American Journal of Pathology, Vol. 157, No. 2, August 2000 Copyright © American Society for Investigative Pathology 377