NPM-ALK–dependent expression of the transcription factor CCAAT/enhancer binding protein in ALK-positive anaplastic large cell lymphoma

CCAAT/enhancer binding protein (C/EBP ) is one of a 6-member family of C/EBPs. These transcription factors are involved in the regulation of various aspects of cellular growth and differentiation. Although C/EBP has important functions in Band T-cell differentiation, its expression has not been well studied in lymphoid tissues. We, therefore, analyzed its expression by immunohistochemistry and Western blot in normal lymphoid tissues and in 248 wellcharacterized lymphomas and lymphoma cell lines. Nonneoplastic lymphoid tissues and most B-cell, T-cell, and Hodgkin lymphomas lacked detectable levels of C/EBP . In contrast, most (40 of 45; 88%) cases of ALK-positive anaplastic large cell lymphoma (ALCL) strongly expressed C/EBP . Western blot analysis confirmed C/EBP expression in the ALK-positive ALCLs and demonstrated elevated levels of the LIP isoform, which has been associated with increased proliferation and aggressiveness in carcinomas. Transfection of Ba/F3 and 32D cells with NPM-ALK and a kinase-inhibitable modified NPMALK resulted in the induction of C/EBP and demonstrated dependence on NPMALK kinase activity. In conclusion, we report the constitutive expression of C/EBP in ALK-positive ALCL and show its relationship to NPM-ALK. We suggest that C/EBP is likely to play an important role in the pathogenesis and unique phenotype of this lymphoma. (Blood. 2006; 108:2029-2036)