An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma

• Published in: Leukemia Vol. 32; no. 1; pp. 92 - 101
• Main Authors: Lollies, A, Hartmann, S, Schneider, M, Bracht, T, Weiß, A L, Arnolds, J, Klein-Hitpass, L, Sitek, B, Hansmann, M-L, Küppers, R, Weniger, M A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2018; Nature Publishing Group
• Subjects: 13; 13/31; 13/44; 13/51; 13/89; 13/95; 631/45/612/822; 631/67/1990/291/1556; 631/67/1990/291/1621; 631/67/395; 631/80/86; 82; Activator protein 1; Anaplastic large-cell lymphoma; B-cell lymphoma; Basic-Leucine Zipper Transcription Factors - genetics; Cancer Research; Carcinogenesis - genetics; Carcinogenesis - pathology; Care and treatment; CD30 antigen; Cell Line, Tumor; Cell Proliferation - genetics; Cell Survival; Chromatin; Critical Care Medicine; Development and progression; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Genetic aspects; Health aspects; Hematology; Hodgkin Disease - genetics; Hodgkin Disease - pathology; Hodgkin's lymphoma; Humans; Immunoprecipitation; Intensive; Interleukin 13; Internal Medicine; Janus kinase 2; Janus Kinase 2 - genetics; JunB protein; Leucine; Leucine zipper proteins; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphoma, Large-Cell, Anaplastic - genetics; Lymphoma, Large-Cell, Anaplastic - pathology; Lymphomas; Mass spectrometry; Mass spectroscopy; Medicine; Medicine & Public Health; Myc protein; Oncogenes - genetics; Oncology; original-article; Physiological effects; Promoter Regions, Genetic - genetics; Proteins; Proto-Oncogene Proteins c-myc - genetics; RNA, Small Interfering - genetics; Signal Transduction - genetics; Signaling; STAT Transcription Factors - genetics; Survival; Transcription Factor AP-1 - genetics; Transcription factors; Transcriptional Activation - genetics; Up-Regulation - genetics
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.203

Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30 + lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30 + diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein. Mass spectrometry and co-immunoprecipitation established interactions of BATF3 with JUN and JUNB in cHL and ALCL lines. BATF3 knockdown using short hairpin RNAs was toxic for cHL and ALCL lines, reducing their proliferation and survival. We identified MYC as a critical BATF3 target and confirmed binding of BATF3 to the MYC promoter. JAK/STAT signaling regulated BATF3 expression, as chemical JAK2 inhibition reduced and interleukin 13 stimulation induced BATF3 expression in cHL lines. Chromatin immunoprecipitation substantiated a direct regulation of BATF3 by STAT proteins in cHL and ALCL lines. In conclusion, we identified STAT-mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas.