AP-1 family transcription factors: a diverse family of proteins that regulate varied cellular activities in classical hodgkin lymphoma and ALK+ ALCL

Abstract

Classical Hodgkin lymphoma (cHL) and anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) are B and T cell lymphomas respectively, which express the tumour necrosis factor receptor superfamily member, CD30. Another feature shared by cHL and ALK+ ALCL is the aberrant expression of multiple members of the activator protein-1 (AP-1) family of transcription factors which includes proteins of the Jun, Fos, ATF, and Maf subfamilies. In this review, we highlight the varied roles these proteins play in the pathobiology of these lymphomas including promoting proliferation, suppressing apoptosis, and evading the host immune response. In addition, we discuss factors contributing to the elevated expression of these transcription factors in cHL and ALK+ ALCL. Finally, we examine therapeutic strategies for these lymphomas that exploit AP-1 transcriptional targets or the signalling pathways they regulate.

Keywords: ALK+ ALCL; Activator protein-1; CD30; Hodgkin; Lymphoma.

Fig. 1

AP-1 proteins are bZip domain-containing transcription factors that comprise four subfamilies. a Cartoons illustrating the relative size and location of the basic leucine zipper (bZip) domain in representative AP-1 proteins from each of the different subfamilies. Protein size and the location of the bZip were determined using the Conserved Domain Database [152] (CDD v3.18) at the National Center for Biotechnology Information (NCBI) website. b Representative AP-1 family members from the Jun, Fos, ATF, and Maf subfamilies are shown

Fig. 2

Functions of AP-1 family proteins in cHL and/or ALK+ ALCL. The major cellular activities regulated by AP-1 family proteins, and their transcriptional targets mediating these effects, in cHL and/or ALK+ ALCL are illustrated. Specific details are described in the text

Fig. 3

Therapies targeting AP-1 regulated genes in cHL and/or ALK+ ALCL. Therapies targeting the protein products of AP-1 transcriptional targets in cHL and/or ALK+ ALCL are highlighted. These include the small molecule tyrosine kinase inhibitor, Imatinib, which targets PDGFRβ, blocking antibodies that interfere with PD-1/PD-L1 interaction (Nivolumab, Pembrolizumab), a bispecfic antibody that recruits NK cells to cells expressing CD30 (AFM13), and an antibody-toxin conjugate which targets CD30-positive cells (Brentuximab Vedotin). Additional details are provided in the text