Biology subjects

Payton, J. E.

Publications and source records attributed to Payton, J. E..

6 recordsLinked to original sources

bioRxiv2025

Single Cell Resolution Tracking of Cutaneous T-Cell Lymphoma Reveals Clonal Evolution in Disease Progression

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multi-omics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. We present here a comprehensive multi-omics view of CTCL clonal evolution, incorporating exome, whole genome, epigenome, bulk-, single cell (sc) VDJ-, and scRNA-sequencing of 114 clinically annotated serial skin, peripheral blood, and lymph node samples from 35 CTCL patients. We leveraged this extensive dataset to define the molecular underpinnings of CTCL progression in individual patients at single cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified a large number of recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, PI3K signaling, and PD-1 checkpoint pathways as evasion tactics deployed by malignant T cells. We also identified a gain of function mutation in STAT3 (D661Y) and demonstrated by CUT&RUN-seq that it enhances binding to transcription start sites of genes in Rho GTPase pathways, which we previously reported to have activated chromatin and increased expression in HDACi-resistant CTCL. These data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. A striking number of progression-associated mutations occurred in chromatin methylation modifiers, including EZH2, suggesting that EZH1/2 inhibition may also benefit patients with CTCL. Knowledge of these molecular changes should be leveraged for improved disease monitoring, biomarker-informed clinical trial design, and new therapeutic strategies in this challenging and incurable cancer.

cancer biology↗

bioRxiv2024

LAIR1 prevents excess inflammatory tissue damage in S. aureus skin infection and Cutaneous T-cell Lymphoma

Patients with cutaneous T cell lymphoma (CTCL) experience high morbidity and mortality due to S. aureus skin infections and sepsis, but the causative immune defect is unclear. We previously identified high levels of LAIR2, a decoy protein for the inhibitory receptor LAIR1, in advanced CTCL. Mice do not have a LAIR2 homolog, so we used Lair1 knock-out (KO) mice to model LAIR2 overexpression. In a model of subcutaneous S. aureus skin infection, Lair1 KO mice had significantly larger abscesses and areas of dermonecrosis compared to WT. Lair1 KO exhibited a pattern of increased inflammatory responses in infection and sterile immune stimulation, including increased production of proinflammatory cytokines and myeloid chemokines, neutrophil ROS, and collagen/ECM remodeling pathways. Notably, Lair1 KO infected skin had a similar bacterial burden and neutrophils and monocytes had equivalent S. aureus phagocytosis compared to WT. These findings support a model in which lack of LAIR1 signaling causes an excessive inflammatory response that does not improve infection control. CTCL skin lesions harbored similar patterns of increased expression in cytokine and collagen/ECM remodeling pathways, suggesting that high levels of LAIR2 in CTCL recapitulates Lair1 KO, causing inflammatory tissue damage and compromising host defense against S. aureus infection.

immunology↗

bioRxiv2023

Epigenetic regulation of Leukocyte associated immunoglobulin-like receptors 1 and 2 by interferon signaling in macrophages and T cells

BackgroundInhibitory immune receptors are important for maintaining immune homeostasis. We recently identified epigenetic alterations in two members of this group, LAIR1 and LAIR2, in patients with inflammatory tissue damage and recurrent skin and soft tissue infections. We therefore hypothesized that the expression of LAIR1 and LAIR2 may be controlled by immune stimuli acting on discrete transcriptional regulatory elements. MethodsWe used flow cytometry, qRT-PCR, and RNAseq to assay LAIR1 and LAIR2 expression in human and murine immune cell subsets at baseline and post-treatment with immune mediators, including type I and II interferons, tumor necrosis factor-alpha (TNF-[a]), and lipopolysaccharide (LPS). Using chromatin immunoprecipitation sequencing (ChIP-seq), we identified candidate transcriptional regulatory elements of LAIR genes and evaluated their regulatory activity using luciferase reporters. ResultsBoth human and murine macrophages significantly upregulate LAIR1 expression as they differentiate from monocytes to macrophages. In response to interferons, LAIR1 protein levels increase, while LPS causes a relative reduction. Regulatory elements flanking LAIR genes exhibit distinct patterns of enhancer activity with variable responses to immune stimuli. These responses are related to discrete sets of transcription factors in inflammatory pathways that correlate with cell-specific LAIR expression patterns. In addition, we identified LAIR1 and LAIR2 regulatory elements that act as foci of 3D genome interactions with other highly active regulatory elements. ConclusionsOur findings define the complex regulatory landscapes of human and mouse LAIR genes and reveal new insights into the transcriptional regulatory mechanisms that control the expression of these important immune modulatory proteins.

immunology↗

bioRxiv2021

Immunosuppression and Outcomes in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) patients rarely have long first remissions (> 5 years) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, short remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing and functional immunologic studies, we characterized 28 Normal Karyotype (NK)-AML patients with >5 year first remissions after chemotherapy (Long First Remissions, LFR) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 years (Standard First Remissions, SFR). Our combined analyses indicated that genetic risk profiling at presentation (as defined by ELN 2017 Criteria) was not sufficient to explain the outcomes of many SFR cases. Single cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T-cells expressed an exhaustion signature and were resistant to activation by T-cell receptor stimulation in the presence of autologous AML cells. T-cell activation could be restored by removing the AML cells, or blocking the inhibitory MHC Class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ T-cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy.

cancer biology↗

bioRxiv2021

Genome-wide analysis of focal DNA hypermethylation in IDH-mutant AML samples

Recurrent mutations in IDH1 or IDH2 in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples with IDH1 or IDH2 mutations, which identified ~4,000 focal regions that were uniquely hypermethylated vs. normal CD34+ cells. These regions had modest, but significant, hypermethylation in AMLs with biallelic TET2 mutations, and 5-hydroxymethylation levels that were dependent on functional TET2, indicating that hypermethylation in these regions is caused by inhibition of TET-mediated demethylation. Focal hypermethylation in IDHmut AMLs occurred in regions with low methylation in normal CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containing IDH and DNMT3AR882 mutations were significantly less hypermethylated, suggesting that methylation in these regions is mediated by DNMT3A. IDHmut-specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, including MYC and ETV6. These results suggest that focal hypermethylation in IDH-mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis.

cancer biology↗

bioRxiv2020

Determining subpopulation methylation profiles from bisulfite sequencing data of heterogeneous samples using DXM

Epigenetic changes, such as aberrant DNA methylation, contribute to cancer clonal expansion and disease progression. However, identifying subpopulation-level changes in a heterogeneous sample remains challenging. Thus, we have developed a computational approach, DXM, to deconvolve the methylation profiles of major allelic subpopulations from the bisulfite sequencing data of a heterogeneous sample. DXM does not require prior knowledge of the number of subpopulations or types of cells to expect. We benchmark DXMs performance and demonstrate improvement over existing methods. We further experimentally validate DXM predicted allelic subpopulation-methylation profiles in four Diffuse Large B-Cell Lymphomas (DLBCLs). Lastly, as proof-of-concept, we apply DXM to a cohort of 31 DLBCLs and relate allelic subpopulation methylation profiles to relapse. We thus demonstrate that DXM can robustly find allelic subpopulation methylation profiles that may contribute to disease progression using bisulfite sequencing data of any heterogeneous sample.

bioinformatics↗