Silencing of the somatic cell-type specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CBP and EP300 as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human iPSCs with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different co-activator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Objective Autologous hematopoietic cell transplantation (AHSCT) improves immunologic dysfunction in patients with Systemic Lupus Erythematosus (SLE). However, the curative potential of this therapy remains uncertain. This study reports outcomes in SLE patients receiving a lymphodepleting reduced intensity regimen for AHSCT in SLE. Methods Eight patients with SLE refractory to treatment, including intravenous cyclophosphamide, were enrolled. Five had lupus nephritis and three central nervous system involvement as primary indications for transplant. Hematopoietic cell mobilization with cyclophosphamide, G-CSF and rituximab was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of concurrent administration of cyclophosphamide, fludarabine, and rituximab. All immunosuppressive medications were discontinued at the start of mobilization and corticosteroids were rapidly tapered after the transplant. Results Five of eight patients achieved a complete response, including a decline in the SLEDAI to zero, which was sustained in four patients for a median of 165 months (range 138–191). One patient achieved a partial response, which was followed by relapse at month 18. Two patients with nephritis and most underlying organ comorbidities had early deaths from infection and multiorgan failure. AHSCT resulted in profound lymphodepletion, followed by expansion of Treg cells and repopulation of naive T and B cells. Patients with CR showed a sustained suppression of the SLE-associated interferon-induced gene signature, marked depletion of memory and plasmablast B cells, and resultant sustained elimination of anti-dsDNA antibody. Conclusion Durable clinical and serologic remissions with suppression in the interferon gene signature can be achieved in refractory SLE following lymphodepleting AHSCT. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT00076752

Chronic graft‐versus‐host disease (cGVHD) is the leading late complication after allogeneic hematopoietic stem cell transplantation (HSCT). Many patients receive multiple lines of systemic therapy until cGVHD resolves, but about 15% remain on systemic treatment for more than 7 years after cGVHD diagnosis. This study describes the clinical and biological factors of patients who present with cGVHD persisting for ≥7 years (persistent cGVHD). Patients with persistent cGVHD (n = 38) and those with cGVHD for <1 year (early cGVHD) (n = 83) were enrolled in a prospective cross‐sectional natural history study. Patients in the persistent cGVHD group were a median of 10.2 years from cGVHD diagnosis (range 7‐27 years). Fifty‐eight percent of persistent cGVHD patients (22/38) were receiving systemic immunosuppression, compared to 88% (73/83) in the early cGVHD group. In multivariable analysis, bone marrow (BM) stem cell source, presence of ENA autoantibodies, higher NIH lung score, higher platelet counts, and higher IgA levels were significantly associated with persistent cGVHD. A high sensitivity panel of serum biomarkers including seven cytokines diagnostic for cGVHD was analyzed and showed significantly lower levels of BAFF and CXCL10 in patients with persistent cGVHD. In conclusion, standardly accepted clinical measures of disease severity may not accurately reflect disease activity in patients with persistent cGVHD. However, many patients with persistent cGVHD are still receiving systemic immunosuppression despite lacking evidence of disease activity. Development of reliable clinical biomarkers of cGVHD activity may help guide future systemic treatments.