Fig. 6

Proposed model for the postulated functions of ARTD9 and DTX3L in DLBCLs. ARTD9 and DTX3L act as novel oncogenic survival factors in relapsed or refractory DLBCL. Constitutively active IL6/IL6R-JAK1-STAT3, oncogenic IFN/IFNGR-JAK1/2-STAT1 and/or IL10/IL10R-JAK1-TYK2-autocrine signaling in HR-DLBCL causes overexpression of ARTD9 and DTX3L, which in turn, further stimulates the phosphorylation of STAT1 on Y701 and subsequently the enhanced expression of STAT1α dependent proto-oncogenes (i.e., ARTD8, ARTD9, DTX3L, IRF2, BCL6, BCL2). Both ARTD9 and DTX3L might also enhance the transcription of DNA damage repair/response genes upon treatment of tumors with genotoxic chemotherapeutic agents [548]. Conversely, ARTD9 and DTX3L repress together with STAT1β the transcriptional activation of tumor suppressor IRF1 and TP53 [470, 471]. Overexpression of ARTD9 inhibits intrinsic and extrinsic IFNγ-STAT1-IRF1/p53-mediated cell death pathways while simultaneously enhancing the STAT1-dependent IRF2-mediated proliferation and BCL6-BCL2 mediated survival pathways. As a consequence ARTD9 induces an oncogenic switch in STAT1 from a tumor suppressor to an oncogene and mediates proliferation, survival and chemo-resistance in HR-DLBCL. Pharmaceutical inhibition of ARTD9 in HR-DLBCL associated with constitutively active STAT1 signaling might therefore reactivate the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1/p53 axes and reverses chemo-resistance in HR-DLBCL. In addition, endogenous overexpression of DTX3L and/or ARTD9 might also be associated with lymphocytes migration and may promote the dissemination of malignant B cells in high-risk DLBCL in vivo, potentially dependent on STAT3 or PI3K/AKT/mTORC1 signaling [471]. DTX3L and/or ARTD9 might form specific complexes with non-canonical STAT1:STAT3 heterodimers and activate a migration-specific signaling and gene expression program in HR-DLBCL. Finally, oncogenic. ARTD9/DTX3L-STAT1α signaling might upregulate immunomodulatory genes and may help the tumors to escape the attack by the immune system (immunoediting) [470, 471, 473]. Conversely, ARTD9 and DTX3L together with STAT1β might repress the transcriptional activation of genes involved in immune surveillance [470, 471, 473]. Adapted from REF: [470, 471]. Abbreviations: ARTD ADP-ribosyltransferase Diphteria toxin-like, DTX3L deltex (DTX)-3-like E3 ubiquitin ligase, STAT signal transducer and activator of transcription, ISG interferon stimulated gene, IL interleukin, JAK Janus kinase, TYK2 tyrosine kinase 2, IRF interferon-regulatory factor, BCL6 B cell lymphoma protein 6, BCL2 B cell lymphoma protein 2