IRF4 is essential for the differentiation and effector functions of many immune cell populations in response to pathogen. Within the B cell compartment, IRF4 is a critical inducer of plasma cell (PC) differentiation and deregulation in IRF4 activity has been associated with multiple pathologies ranging from autoimmunity to B cell malignancies. Among B cell malignancies, the ABC subtype of diffuse-large B cell lymphoma (DLBCL) is particularly aggressive and is characterized by deregulations in the molecular networks controlling PC differentiation, including IRF4. A detailed understanding of the molecular mechanisms that control IRF4 activity can provide critical insights for the development of novel therapies for the treatment of ABC-DLBCL. Previously, our lab discovered that IRF4 is phosphorylated by ROCK2, a serine-threonine kinase, during Th17 differentiation and that this ROCK2-pIRF4 axis drives aberrant IL-17 and IL- 21 production in several autoimmune models. Consistent with this finding, pharmacological inhibition of ROCK with Fasudil ameliorates disease in lupus-prone MRL/lpr and NZB/W F1 mice and in arthritic Def6-/- DO11.10 mice. While previous studies delineated the ROCK-pIRF4 axis in Th17 cells, we are exploring the possibility that ROCKs play more global roles in immune regulation. Supporting this notion, we found that stimulation of B cells with aCD40 and IL-21 leads to the activation of ROCK2 and to the phosphorylation of IRF4. We furthermore discovered that IRF4 is selectively phosphorylated in ABC-DLBCLs, but not in other DLBCL subtypes, including GCB-DLBCLs. Importantly, we have assessed the functional relevance of ROCK activity in ABC-DLBCL and discovered that inhibition of ROCK induces selective lethality in ABC-DLBCL. We thus now propose that phosphorylation of IRF4 by ROCK2 in ABC-DLBCL promote the oncogenic function of IRF4 and that ROCK inhibition could represent a novel therapeutic approach for ABC-DLBCL. The specific goals of this proposal are: 1) To dissect the role of ROCK2 activation in ABC-DLBCL, 2) To investigate the functional consequences of IRF4 phosphorylation in ABC-DLBCL, 3) To broadly assess the role of ROCK2 activation and IRF4 phosphorylation in ABC-DLBCL. Given that ROCK inhibitors have already shown benefits in clinical trials for cardiovascular disorders while exhibiting only minimal side effects, the knowledge derived from the studies described in this proposal could be rapidly translated into a novel therapeutic regimen for the treatment of ABC-DLBCL.
These studies will delineate the signaling pathways, which if deregulated, can lead to the pathogenesis of Activated B Cell-like (ABC) DLBCL, a particularly aggressive subtype of lymphoma. In particular, these studies will provide critical insights into th role of the ROCK- pIRF4 axis in this disease. Given that ROCK inhibitors have already been used for the treatment of cardiovascular disorders and are well tolerated, the knowledge derived from these studies could be rapidly translated into novel therapeutic regimens for the treatment of ABC-DLBCL.
| Manni, Michela; Gupta, Sanjay; Ricker, Edd et al. (2018) Regulation of age-associated B cells by IRF5 in systemic autoimmunity. Nat Immunol 19:407-419 |
| Ricker, Edd; Chowdhury, Luvana; Yi, Woelsung et al. (2016) The RhoA-ROCK pathway in the regulation of T and B cell responses. F1000Res 5: |
