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

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Abstract
CCAAT/enhancer binding protein β (C/EBPβ) 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/EBPβ has important functions in B- and 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 well-characterized lymphomas and lymphoma cell lines. Nonneoplastic lymphoid tissues and most B-cell, T-cell, and Hodgkin lymphomas lacked detectable levels of C/EBPβ. In contrast, most (40 of 45; 88%) cases of ALK-positive anaplastic large cell lymphoma (ALCL) strongly expressed C/EBPβ. Western blot analysis confirmed C/EBPβ 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 NPM-ALK resulted in the induction of C/EBPβ and demonstrated dependence on NPM-ALK kinase activity. In conclusion, we report the constitutive expression of C/EBPβ in ALK-positive ALCL and show its relationship to NPM-ALK. We suggest that C/EBPβ is likely to play an important role in the pathogenesis and unique phenotype of this lymphoma.