The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma

Abstract

Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+ and ALK– anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK+ ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17–, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK+ ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3.

The new biology of PTCL‐NOS and AITL: current status and future clinical impact

“…ALCL showed high expression of IL17A, IL17F and RORct transcripts, which are associated with normal Th17 cells (Iqbal et al, 2010). This has been substantiated in other work: analysis of ALCL cell lines showed that basic leucine zipper ATF-like transcription factor (BATF) and BATF3 established a Th17 gene expression pattern in ALCL cell lines (Schleussner et al, 2018). One effect of the t(2;5)(p23;q35) chromosomal translocation, which is found in ALK + ALCL, is to suppress GATA3 and Th2 gene expression while promoting Th17 genes (Matsuyama et al, 2011).…”

BATF acts as an oncogene in non‑small cell lung cancer

“…These results suggested that BATF may regulate NSCLC cell proliferation and apoptosis in vitro. A number of studies provide support that BATF may play an important role in the development of different types of cancer, including colon cancer, lymphoma and multiple myeloma (16)(17)(18).…”

“…Regulation of the AP-1 gene effects cell survival, differentiation and proliferation (14,15). An increasing number of studies suggest that BATF may affect cancer development (16)(17)(18). However, the functional mechanisms of BATF in NSCLC are poorly understood.…”

The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

“…BATF-3 is highly expressed in CD30 + CHL, although it relies on additional AP-1 cofactors to dimerize, as BATF family members lack a transcriptional activation domain [ 89 , 90 , 91 ]. Indeed, co-immunoprecipitation and mass spectrometry revealed that BATF-3 directly interacts with JUN and JUNB in HRS cells, which in turn activates MYC transcription by directly binding to its promoter [ 88 , 92 ]. This novel oncogenic STAT–BATF-3/JUN–MYC signalling axis seems to be essential for HRS cell survival ( Figure 2 ) [ 88 ].…”

“…In particular, JUNB or c-JUN expression protects cells from apoptosis, thereby enhancing cellular proliferation and colony formation [ 23 , 71 , 121 , 123 , 125 ]. Given the activity of c-JUN, JUNB, FRA-2, and ATF-3 in ALCL, it is likely that other AP-1 activating factors play a role in lymphomagenesis [ 92 , 118 ].…”