Lawrence B, Perez-Atayde A, Hibbard M K, Rubin B P, Dal Cin P, Pinkus J L, Pinkus G S, Xiao S, Yi E S, Fletcher C D, Fletcher J A
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Am J Pathol. 2000 Aug;157(2):377-84. doi: 10.1016/S0002-9440(10)64550-6.
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 approximately 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 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.
炎性肌纤维母细胞瘤（IMTs）是一种肿瘤性间充质增生，其特征为主要由淋巴细胞和浆细胞组成的炎性浸润。一些IMTs中的肌纤维母细胞含有涉及ALK受体酪氨酸激酶基因座区域（染色体带2p23）的染色体重排。ALK——其表达通常局限于神经组织——在具有2p23重排的IMT细胞中显著表达。我们现在报告一种在IMTs中反复出现的致癌机制，其中原肌球蛋白（TPM）N端卷曲螺旋结构域与ALK C端激酶结构域融合。我们克隆了两个ALK融合基因，TPM4-ALK和TPM3-ALK，它们编码约95-kd的融合癌蛋白，其特征为组成型激酶活性和酪氨酸磷酸化。在其他IMTs中，免疫组织化学和分子相关性表明非TPM ALK癌蛋白主要位于细胞质或细胞核，这可能取决于ALK融合伴侣的亚细胞定位。值得注意的是，最近在间变性淋巴瘤中报道了一种TPM3-ALK癌基因，因此TPM3-ALK是第一个已知的在体内可转化人间充质和淋巴样细胞系的融合癌基因。
