The human genome contains regulatory DNA elements, known as enhancers, that can activate gene transcription over long chromosomal distances. Here, we showed that enhancer distance can be critical for gene silencing. We demonstrated that linear recruitment of the normally distal strong HBB enhancer to developmentally silenced embryonic HBE or fetal HBG promoters through deletion or inversion of intervening DNA sequences led to strongly reactivated expression in adult erythroid cells and ex vivo differentiated hematopoietic stem and progenitor cells. A similar observation was made for the HBA locus in which deletion-to-recruit of the distal enhancer strongly reactivated embryonic HBZ expression. Overall, our work assigned function to seemingly nonregulatory genomic segments; by providing linear separation, they may support genes to autonomously control their transcriptional response to distal enhancers.

Chronic lymphocytic leukemia (CLL) is a disease of great clinical and biologic heterogeneity; some patients are observed for years without symptoms, whereas others rapidly develop progressive disease requiring treatment. With therapy, some patients eventually develop resistant CLL or transformation to an aggressive form. Across this spectrum, patients experience immune dysfunction associated with increased risk for infection and second cancers, contributing to morbidity and mortality of the disease. The ultimate therapeutic bull's-eye for CLL is to eliminate the disease and achieve immune restoration. Disease elimination can potentially be achieved for a fraction of patients treated first line with chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab), for some patients who receive time-limited combined targeted therapy, and for some patients with relapsed/refractory CLL who undergo allogeneic stem cell transplant. Long-term immune restoration for these patients is elusive. Current targeted therapies, including Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors and CD20 monoclonal antibodies used in combinations, can produce exceptional therapeutic outcomes, which are improving survival for patients who need treatment. Although clear progress has been made toward highly effective CLL management, appreciation of the full impact of these advances will require time because of the chronic nature of the disease. In addition, it is imperative to ensure global access to the targeted therapies, emphasizing the need for harmonized regulatory oversight and affordable treatment options worldwide. Here, we discuss research and collaborative strategies to refine the use of targeted agents to eliminate CLL and restore immune function for all affected individuals.

Relapsed/refractory T-cell acute lymphoblastic leukemia (ALL; T-ALL)/lymphoma (LBL) represent a significant unmet medical need. WU-CART-007 is a CD7-targeting, allogeneic, fratricide-resistant chimeric antigen receptor T-cell product generated from healthy donor T cells. WU-CART-007 was evaluated in a phase 1/2 study with a 3+3 dose-escalation design followed by cohort expansion in relapsed/refractory T-ALL/LBL. Patients received 1 infusion of WU-CART-007 after standard or enhanced lymphodepleting chemotherapy. The primary objectives, to characterize safety and assess the composite complete remission rate, were met. Of 28 patients enrolled, 13 received the recommended phase 2 dose (RP2D) of 900 × 106 cells of WU-CART-007 with enhanced lymphodepletion. The most common treatment-related adverse event was cytokine release syndrome (88.5%; 19.2% grade 3-4). Two grade 1 immune effector cell-associated neurotoxicity syndrome events (7.7%) and 1 grade 2 acute graft-versus-host disease event occurred (3.8%). One grade 2 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome was observed. Among the 11 patients evaluable for response at the RP2D who received enhanced lymphodepleting chemotherapy, the overall response rate was 90.9%, and the composite complete remission rate was 72.7%. WU-CART-007 at the RP2D demonstrated a high response rate in patients with relapsed/refractory T-ALL/LBL and has the potential to provide a new treatment option. This trial was registered at www.ClinicalTrials.gov as #NCT04984356.