NPM-ALK-dependent expression of the transcription factor CCAAT/enhancer binding protein beta in ALK-positive anaplastic large cell lymphoma.
CCAAT/enhancer binding protein beta (C/EBPbeta) 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/EBPbeta 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/EBPbeta. In contrast, most (40 of 45; 88%) cases of ALK-positive anaplastic large cell lymphoma (ALCL) strongly expressed C/EBPbeta. Western blot analysis confirmed C/EBPbeta 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/EBPbeta and demonstrated dependence on NPM-ALK kinase activity. In conclusion, we report the constitutive expression of C/EBPbeta in ALK-positive ALCL and show its relationship to NPM-ALK. We suggest that C/EBPbeta is likely to play an important role in the pathogenesis and unique phenotype of this lymphoma.
Quintanilla-Martinez
Leticia
L
Institute of Pathology, GSF-National Research Center for Health and Environment, Neuherberg, Germany.
Pittaluga
Stefania
S
Miething
Cornelius
C
Klier
Margit
M
Rudelius
Martina
M
Davies-Hill
Theresa
T
Anastasov
Natasa
N
Martinez
Antonio
A
Vivero
Angelica
A
Duyster
Justus
J
Jaffe
Elaine S
ES
Fend
Falko
F
Raffeld
Mark
M
D000077548:Anaplastic Lymphoma Kinase; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008221:Lymphoid Tissue / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases; D014162:Transfection
D022782:CCAAT-Enhancer-Binding Protein-beta; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases