Two-thirds of anaplastic large-cell lymphomas (ALCLs) express NPM-ALK or a variant ALK fusion (AT1C-ALK, CLTC-ALK, TFG-ALK, or TPM3-ALK). The presence of truncated, constitutively active ALK fusion proteins has been thought to be restricted to ALCL. Inflammatory myofibroblastic tumors (IMTs) occur primarily in the soft tissue and viscera of children and young adults, and are spindle cell proliferations composed of bland-appearing myofibroblasts and a variably collagenous stroma admixed w th inflammatory cells. Controversy has existed as to the reactive vs. neoplastic nature of IMTs, which are often indolent and curable by conservative resection. Abnormalities at chromosome 2p23 have recently been identified in IMTs, and ALK rearrangement has been demonstrated by FISH. To examine the role of ALK fusions in IMT, we perfonred anti-ALK immunostaining on 68 cases of IMT, identifying 42 (61.8%) to be ALKpositive. The ALK staining in all cases was confined to the cytoplasm of the myofibroblastic tumor cells, suggesting that none expressed NPM-ALK (which is locali; ed in the cytoplasm and nucleoplasm/nucleoli). To determine the identity of the ALK fusions expressed in IMT, we performed 5' RACE to amplify the ALK partner genes, analyzing 11 cases with frozen material available (6 of which were ALK-positive by staining). Tlree of these 6 ALK-positive cases expressed an ALK fusion containing the N-terminal 221 amino acids (aa) of TPM4 - a nonmuscle tropomyosin encoded at chromosome 19pl.i.l that is highly homologous to TPM3. Another two cases expressed the CLTC-ALK fusion formed by t(2;17)(p23;q23), which incorporates 1,634 residues of the 1,675-aa clathrin heavy chain and occurs also in ALCL. The remaining one of these ALK-positive IMTs expressed a novel fusion in which the N-terminal 867 residues of the 3,228-aa nuclear pore protein Ran binding protein 2 (RanBP2, also known as Nup358), encoded at 2qll-13, was fused to ALK. IMT tumor cells expressing RanBP2-ALK exhibited a unique ring-like nuclear membrane-associated ALK immunostaining pattern presumably due to associât on of the fusion protein with normal RanBP2 at the nuclear pore. Studies are in progress to determine the exact incidence of TPM4-ALK, CLTC-ALK, and RanBP2-ALK in IMT to determine whether other ALK chimeric proteins are expressed, and to correlate ALK fusion protein expression with clinical-pathological characteristics of IMT.
|Original language||English (US)|
|Issue number||11 PART I|
|State||Published - 2000|
ASJC Scopus subject areas
- Cell Biology