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Active regulatory elements recruit cohesin to establish cell specific chromatin domains.
As the 3D structure of the genome is analysed at ever increasing resolution it is clear that there is considerable variation in the 3D chromatin architecture across different cell types. It has been proposed that this may, in part, be due to increased recruitment of cohesin to activated cis-elements (enhancers and promoters) leading to cell-type specific loop extrusion underlying the formation of new sub-TADs. Here we show that cohesin correlates well with the presence of active enhancers and that this varies in an allele-specific manner with the presence or absence of polymorphic enhancers which vary from one individual to another. Using the alpha globin cluster as a model, we show that when all enhancers are removed, peaks of cohesin disappear from these regions and the erythroid specific sub-TAD is no longer formed. Re-insertion of the major alpha globin enhancer (R2) is associated with re-establishment of recruitment and increased interactions. In complementary experiments insertion of the R2 enhancer element into a "neutral" region of the genome recruits cohesin, induces transcription and creates a new large (75 kb) erythroid-specific domain. Together these findings support the proposal that active enhancers recruit cohesin, stimulate loop extrusion and promote the formation of cell specific sub-TADs.
Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A.
Chromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q ('chr. 21amp') in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
Measure selection for an electronic patient-reported outcome (ePRO) system for CAR T-cell therapy patients: a modified Delphi consensus study
Background: Chimeric Antigen Receptor (CAR) T-cell therapies are effective for treating haematological cancers but carry risks of toxicity and substantial symptom burden. Patient-reported outcomes (PROs) could significantly enhance clinical management for patients undergoing these treatments. However, guidance on selection of PRO measures for monitoring adverse event and quality of life after CAR T-cell therapy is limited. This study aimed to achieve consensus among patients and healthcare professionals on the selection of PRO measures for an electronic PRO (ePRO) system for CAR T-cell therapy clinical settings. Methods: Two-round modified Delphi study (online survey and consensus meeting) conducted from December 2023 to January 2024 to select PRO measures for the ePRO system, guided by a conceptual framework with four measurement domains: symptom burden, impacts of cancer and CAR T-cell therapy, treatment tolerability, and health-related quality of life (HRQoL). Database searches (PubMed, ePROVIDE, COSMIN, and COMET) and licensing websites of cancer-specific PRO measures identified 113 PRO measures. Measures were pre-specified for treatment tolerability and HRQoL domains and concept mapping established conceptual coverage for the remaining domains. Seven PRO measures were shortlisted and prespecified inclusion thresholds and stopping criteria guided Delphi panel selection. Registration: ISRCTN11232653. Findings: Nineteen participants (5 CAR T-cell patients, 14 healthcare professionals/researchers) recruited from a UK National Health Service (NHS) cellular therapy centre and professional networks took part in Round One (Delphi online survey). Shortlisted measures were rated for relevance, comprehensiveness, and ease of understanding for the symptom burden and impacts of cancer and CAR T-cell treatment domains. Consensus was achieved after Round One, precluding the requirement for Round 2 (consensus meeting). The Symptom Burden Questionnaire™ (SBQ™) and the Quality of Life in Adult Cancer Survivors (QLACS) were selected to represent the Symptom Burden and Impacts domains, respectively. These measures, EQ5D-5L, measuring HRQoL, and Functional Assessment of Chronic Illness Therapy–Item GP5 (FACT-GP5), single-item global indicator of cancer treatment tolerability, will be included in the ePRO system. Interpretation: In the absence of guidance on PRO measure selection for CAR T-cell therapies, consensus-based methods represent an important step towards use of PROs with this clinical population. Modest sample size and representativeness of the patient subgroup are limitations of this study. Funding: This study is funded by the National Institute for Health and Care Research (NIHR) Blood and Transplant Research Unit in Precision Cellular Therapeutics (NIHR203339). The views expressed are those of the authors and not necessarily those of the NIHR, NHS Blood and Transplant, or the Department of Health and Social Care.
Genome-Wide Association Studies of Down Syndrome Associated Congenital Heart Defects Suggests a Genetically Heterogeneous Risk for CHD in DS.
Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40%-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n = 886: atrioventricular septal defects (AVSD), n = 438; atrial septal defects (ASD), n = 122; ventricular septal defects (VSD), n = 170; other types of CHD, n = 156) and DS with a structurally normal heart (DS + NH, n = 572). We performed four genome-wide association study (GWAS) for common variants (MAF > 0.05) comparing DS with CHD, stratified by CHD-subtype, to DS + NH controls. Although no SNP achieved genome-wide significance, multiple loci in each analysis achieved suggestive significance (p
Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia.
Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.
Tumor-Infiltrating Clonal Hematopoiesis.
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear. METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors. RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth. CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).