The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone (DZ) that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, which include the DZ signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a data set from the cohort of British Columbia Cancer (BCC) (n = 804). Through the 1050 patient samples on which DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to have germinal center B-cell–like (GCB) DLBCL, activated B-cell–like (ABC) DLBCL, and DZsig-positive (DZsigpos) DLBCL, respectively, with the highest prevalence of ABC-DLBCL, differing significantly from the BCC result (P < .001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with 2-year overall survival rates of 88%, 75%, and 66%, respectively (P < .0001), with patients with DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes after rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all, P < .05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas.

Antigen encounter directs CD4⁺ T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4⁺ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4⁺ T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.

The revised WHO classification newly defined the entities “High‐grade B‐cell lymphoma with MYC and BCL2, and/or BCL6 rearrangements (HGBL‐DH/TH)” and “HGBL, NOS.” Standard immunochemotherapy for diffuse large B‐cell lymphoma (DLBCL), R‐CHOP, is insufficient for HGBL patients, and there are currently no optimized therapeutic regimens for HGBL. We previously reported that CCND3, which encodes cyclin D3, harbored high mutation rates in Burkitt lymphoma (BL), HGBL and a subset of DLBCL. Furthermore, the knockdown of cyclin D3 expression was toxic to germinal center (GC)‐derived B‐cell lymphomas. Thus, the fundamental function of cyclin D3 is important for the pathogenesis of GC‐derived B‐cell lymphoma. We herein used two structurally different CDK4/6 inhibitors, palbociclib and abemaciclib, and examined their suppressive effects on cell proliferation and their ability to induce apoptosis in various aggressive B‐cell lymphoma cell lines. The results obtained demonstrated that abemaciclib more strongly suppressed cell proliferation and induced apoptosis in GC‐derived B‐cell lymphoma cell lines than the control, but only slightly inhibited those features in activated B‐cell (ABC)‐like DLBCL cell lines. Palbociclib exerted partial or incomplete effects compared with the control and the effect was intermediate between abemaciclib and the control. Moreover, the effects of abemaciclib appeared to depend on cyclin D3 expression levels based on the results of the expression analysis of primary aggressive B‐cell lymphoma samples. Therefore, abemaciclib has potential as a therapeutic agent for aggressive GC‐derived B‐cell lymphomas.

The capacity for T cells to become activated and clonally expand during pathogen invasion is pivotal for protective immunity. Our understanding of how T cell receptor (TCR) signaling prepares cells for this rapid expansion remains limited. Here we provide evidence that the E3 ubiquitin ligase Cullin-4b (Cul4b) regulates this process. The abundance of total and neddylated Cul4b increased following TCR stimulation. Disruption of Cul4b resulted in impaired proliferation and survival of activated T cells. Additionally, Cul4b-deficient CD4⁺ T cells accumulated DNA damage. In T cells, Cul4b preferentially associated with the substrate receptor DCAF1, and Cul4b and DCAF1 were found to interact with proteins that promote the sensing or repair of damaged DNA. While Cul4b-deficient CD4⁺ T cells showed evidence of DNA damage sensing, downstream phosphorylation of SMC1A did not occur. These findings reveal an essential role for Cul4b in promoting the repair of damaged DNA to allow survival and expansion of activated T cells.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a newly recognized disease entity characterized by EBV-positive atypical B-cell proliferation. EBVMCU is a localized self-limited disease that affects mucosa and skin, especially the oral cavity. EBVMCU develops in immunosuppressive patients, such as those with methotrexate (MTX)-administrated rheumatoid arthritis (RA). Here we clinicopathologically analyzed 12 EBVMCU patients in a single institution. All cases were administrated MTX for RA, and five cases occurred in the oral cavity. All cases except one had demonstrated spontaneous regression after withdrawal of the immunosuppressive agent. We found 4 of 5 cases in the oral cavity had preceding traumatic events in the same site within a week before the onset of EBVMCU. Although there is no detailed and large study that has analyzed the trigger of EBVMCU, a traumatic event would indeed be a significant trigger for EBVMCU in the oral cavity. The cases were histologically classified; six cases were diffuse large B-cell lymphoma-type, five were polymorphous-type, and one was Hodgkin-like lesion type due to morphological appearance and immunophenotype. The PD-L1 expression was also examined by two antibodies for PD-L1 (E1J2J and SP142). Both antibodies revealed identical results for PD-L1 expression, and three cases were positive for PD-L1. The application of SP142 for evaluating the immune status of lymphomagenesis has also been proposed. Nine of 12 cases were negative for PD-L1, which implies that most EBVMCU cases may be caused by an immunodeficiency, rather than an immune-evasion, mechanism. However, as three cases were positive for PD-L1, immune escape may underly the pathogenesis in a subset of EBVMCU cases.