B cell receptor silencing reveals origin and dependencies of high-grade B cell lymphomas with MYC and BCL2 rearrangements

The B cell receptor (BCR) is critical for mature B cell lymphomas, serving as a therapeutic target. We show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-BCL2 (IGHUND) differ from IGH+ counterparts in germinal center-zone programs, MYC expression, and immune infiltrate. While IGH+ HGBCL-DH-BCL2 favor IGM/IG-Kappa expression, IGHUND counterparts complete IGH isotype switching and IG-Lambda rearrangements. IGHUND lymphomas retain productive IGHV rearrangements and require IGH for optimal fitness. BCR silencing, caused by accelerated IGH turnover and reduced IGH expression, precedes HGBCL-DH-BCL2 onset, inducing RAG1/2-dependent IG light chain editing and facilitating t(8;22)/IGL::MYC translocations. IGHUND HGBCL-DH-BCL2 models exhibit reduced sensitivity to the CD79B-targeting antibody-drug conjugate Polatuzumab-vedotin. Collectively, HGBCL-DH-BCL2 commonly arises from isotype-switched t(14;18)+ germinal center B cells, which edit IG light chains, fueling intra-clonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications

Expression of the lupus associated Pbx1-d isoform induces pro-inflammatory phenotypes in mesenchymal stem cells (MSCs) in a mouse model of lupus

Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease that causes chronic inflammation. It is most prevalent in women, especially in women from minority populations and is heterogeneous. In previous experiments, it has been discovered that mesenchymal stem cells (MSCs) from a lupus-prone mouse strain (Sle1a1) express a defective allele of Pbx1 (Pbx1-d), a gene that controls stemness in MSCs. Sle1a1 MSCs grow faster, differentiate quicker into osteoblasts than the B6 control, and have impaired immunosuppressive function. This data together with a significant decrease in the expression of genes associated with stemness and an increase in expression of genes associated with differentiation suggests that the Pbx1-d allele disrupts the immunoregulatory functions of MSCs. This could contribute to lupus pathogenesis. We aimed to see if Pbx1-d expression in Sle1a1 MSCs increases the expression of genes promoting inflammation and activates the innate immune system. 26 genes were selected that showed an expression fold change greater than 2 in RNA sequencing as compared to B6 control MSCs. Some of the genes belong to metabolic pathways, which we are currently validating by comparing mTOR activation, glucose metabolism and mitochondrial respiration between B6 and Sle1a1 MSCs. Preliminary results suggest a different production of inflammatory cytokines and chemokines by activated Sle1a1 MSCs. Further the supernatants of activated Sle1a1 MSCs favors Th17 polarization and impairs Treg polarization in vitro. MSC cell therapy has been considered to treat lupus. Our studies provide unique insights on how a lupus susceptibility gene impairs MSC direct functions and their interactions with T cells.</jats:p

Metabolic Functions of the Murine Lupus Susceptibility Gene <i>Pbx1</i>

Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease that affects many organ systems. Poorly characterized genetic factors contribute to SLE, in part through the production of autoreactive or inflammatory T cells. Pre-B cell leukemia homeobox 1 (Pbx1) is a transcription factor whose Pbx1-d dominant negative splice isoform is overexpressed in CD4T cells of lupus patients as well as in the NZM2410 lupus-prone mouse as compared to the normal Pbx1-b isoform. Based on gene expression studies comparing murine CD4 T cells overexpressing Pbx1-d to controls, we hypothesize that Pbx1-d enhances cellular metabolism in T cells through the HIF1α and mTORc1 pathways. CD4 T cells expressing Pbx1-d present a higher cellular metabolism and show a higher mTORc1 activation than normal control T cells. Using mesenchymal stem cells, we showed that transfection of Pbx1-d was sufficient to increase glycolysis, a pathway linked to T cell activation. We found that Ddit4, an mTORc1 inhibitor, shows a lower expression in the Pbx1-d-expressing CD4 T cells than in normal T cells. We also discovered that Pbx1-d preferentially binds to the promoter of Ddit4, as well as Egln1 and Egln3, two HIF1a inhibitors. These results suggest that a mechanism by which the Pbx1-d allele contributes to lupus pathogenesis is to enhance CD4 T cell metabolism. Future work will define how Pbx1 controls the immune system and how the function of this transcription factor is linked to cellular metabolism.</jats:p

Relationship of Visual Function with Incident Fall and Mortality among Patients with Anterior Ischemic Optic Neuropathy

The purpose of this study was to determine if worse visual acuity is associated with an increased risk of incident fall or mortality, independent of other relevant cofounders. This was a single-center retrospective cohort study of 428 new cases of anterior ischemic optic neuropathy (AION). Separate Cox proportional hazards models were constructed to evaluate the relationship between either logMAR visual acuity (VA) or legal blindness (20/200 or worse VA) and survival time to (1) encounter for fall, (2) mortality, and (3) a composite adverse outcome. Multivariable models were adjusted for a priori confounders. In adjusted models, a 1-unit increase in logMAR VA was associated with a significantly greater risk of an incident fall (adjusted HR 1.36, 95% CI (1.06&ndash;1.73), p = 0.014) and of mortality (adjusted HR 1.44, 95% CI (1.15&ndash;1.82), p = 0.002). Meeting criteria for legal blindness was also significantly associated with a higher risk of incident fall (HR 1.80, 95% CI (1.05&ndash;3.07), p = 0.032) and mortality (adjusted HR 2.16, 95% CI (1.29&ndash;3.63), p = 0.004). Among patients with AION, worse visual acuity or legal blindness conferred a significantly increased risk of falls and mortality, independent of coexistent comorbidities. Future studies should consider fall reduction interventions for patients with poor vision from severe eye disease such as AION

Feasibility of deploying community health workers to assist with health-related social needs and hypertension in community care clinics

We conducted a pilot study of implementing community health workers (CHWs) to assist patients with hypertension and social needs. As part of clinical care, patients identified as having an unmet need were referred to a CHW. We evaluated changes in blood pressure and needs among 35 patients and conducted interviews to understand participants’ experiences. Participants had a mean age of 54.1 years and 29 were Black. Twenty-six completed follow-up. Blood pressure and social needs improved from baseline to 6 months. Participants reported being accepting of CHWs, but also challenges with establishing a relationship with a CHW and being unclear about their role