Hyperactivated STAT3 in ALK–positive diffuse large B-cell lymphoma with clathrin-ALK fusion

SummaryAnaplastic lymphoma kinase (ALK)–positive large B-cell lymphoma is a rare subtype of diffuse large B-cell lymphoma (DLBCL). Although a few cases of ALK–positive large B-cell lymphoma harbor nucleophosmin–ALK chromosomal translocation similar to ALK–positive anaplastic large cell lymphoma, most reported cases are characterized by t(2;17)(p23;q23) involving the clathrin gene. Here, we report 2 cases of ALK–positive DLBCL. The 2 cases presented similar morphologic features and immunohistochemical characteristics, that is, positivity for ALK, IgA, CD138, and MUM1; weak positivity for CD30 and CD79a; and negativity for CD20. The clathrin–ALK transcript was identified by reverse transcription–polymerase chain reaction, and the sequence was determined by direct sequencing. Recently, the essential role of STAT3 activation as well as STAT 5 activation in nucleophosmin–ALK fusion protein–mediated lymphomagenesis was reported. However, differential effects of ALK–fusion variant proteins on proliferation, transformation, and invasion properties were reported. Thus, we evaluated the phosphorylation status of STAT 3 and STAT 5, and found highly hyperphosphorylated STAT 3 on tyrosine 705 but not STAT 5 in our 2 cases of ALK–positive DLBCL with clathrin–ALK fusion. Furthermore, STAT 5A expression was not detected in either of the ALK–positive DLBCL cases, although 11 of the 36 ALK–negative DLBCL cases revealed STAT 5A expression. Expression of the antiapoptotic proteins survivin and BCL-XL, which were believed to be the targets of STAT 3, was investigated. However, there were no significant associations between expression of survivin or BCL-XL and ALK positivity among the diffuse large B-cell lymphomas. In summary, similar signaling transduction mechanism involving STAT proteins seems to underlie DLBCL harboring the clathrin–ALK or nucleophosmin–ALK fusion gene.