Biology subjects

Sucheston-Campbell, L. E.

Publications and source records attributed to Sucheston-Campbell, L. E..

3 recordsLinked to original sources

bioRxiv2022

Associations of Minor Histocompatibility Antigens with Clinical Outcomes Following Allogeneic Hematopoietic Cell Transplantation

The role of minor histocompatibility antigens (mHAs) in mediating graft versus leukemia (GvL) and graft versus host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT) is recognized but not well-characterized. By implementing improved methods for mHA prediction in two large patient cohorts, this study aimed to comprehensively explore the role of mHAs in alloHCT by analyzing whether (1) the number of predicted mHAs, or (2) individual mHAs are associated with clinical outcomes using multi-variate survival models corrected for multiple testing. Cox proportional hazard results showed that patients with a class I mHA count greater than the population median had an increased hazard of GvHD mortality (HR=1.39, 95%CI 1.01, 1.77, P=0.046). Competing risk analyses identified the class I mHAs DLRCKYISL (gene GSTP), WEHGPTSLL (CRISPLD2) and STSPTTNVL (SERPINF2) were associated with increased GVHD death (HR=2.84, 95%CI 1.52, 5.31, P=0.01), decreased leukemia-free survival (LFS) (HR=1.94,95%CI 1.27, 2.95, P=0.044), and increased disease-related mortality (DRM) (HR=2.32, 95%CI 1.5, 3.6, P=0.008), respectively. One class II mHA YQEIAAIPSAGRERQ (TACC2) was associated with increased risk of treatment-related mortality (TRM) (HR=3.05, 95%CI 1.75, 5.31, P=0.02). WEHGPTSLL and STSPTTNVL were present in conjunction within HLA haplotype B*40:01-C*03:04 and showed a positive dose-response relationship with increased all-cause mortality and DRM and decreased LFS, indicating these two mHAs contribute to risk of mortality in an additive manner. Our study reports the first large scale investigation of the associations of predicted class I and class II mHA peptides with clinical outcomes following alloHCT. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/506092v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1516a9aorg.highwire.dtl.DTLVardef@2db79aorg.highwire.dtl.DTLVardef@170e19aorg.highwire.dtl.DTLVardef@1eb7148_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2022

Vitamin D receptor cistrome-transcriptome analyses establishes quantitatively distinct receptor genomic interactions in African American prostate cancer regulated by BAZ1A

BackgroundAfrican American (AA) prostate cancer (PCa) appears uniquely sensitive to 1,25(OH)2D3 signaling, compared to European American (EA) PCa, but the extent and impact of vitamin D receptor genomic functions remain poorly defined. ResultsA panel of EA and AA prostate epithelial cells (EA: HPr1-AR, LNCaP, AA: RC43N, RC43T, RC77N, RC77T) were analyzed with RIME to reveal the cell-specific composition of the VDR- complex. 1,25(OH)2D3-dependent ATAC-Seq revealed the greatest impact on nucleosome positioning in RC43N and RC43T, with gain of nucleosome-free at enhancer regions. VDR ChIP-Seq identified stronger and more frequent VDR binding in RC43N and RC43T that was enriched for a larger and distinct motif repertoire, than EA cells. VDR binding significantly overlapped with core circadian rhythm transcription factors in AA cell line models. RNA-Seq also revealed significantly stronger 1,25(OH)2D3 dependent VDR transcriptional responses enriched for circadian rhythm and inflammation networks in AA cells. Whilst RC43N was most responsive, RC43T displayed distorted responses. Significantly reduced BAZ1A/SMARCA5 in AA PCa samples was identified, and restored BAZ1A expression uniquely and significantly increased 1,25(OH)2D3-regulated VDR targets in AA cells. These VDR- dependent cistrome-annotated genes were also uniquely and most significantly identified in three cohorts of AA PCa patients. ConclusionThese data suggest VDR transcriptional control in the prostate is more potent and dynamic in AA men, and primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmentally-regulated serum vitamin D3 levels suppress these actions. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes including stress responses, access to quality early detection and treatment, social determinants and that collectively contribute to PCa health disparities.

cancer biology↗

bioRxiv2017

The miR-96/RARγ signaling axis governs androgen signaling and PCa progression

Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RAR{gamma}), are commonly reduced in prostate cancer (PCa). Therefore we sought to establish the cellular and gene regulatory consequences of reduced RAR{gamma} expression, and determine RAR{gamma} regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RAR{gamma} levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RAR{gamma} cistrome which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RAR{gamma} to regulate androgen signaling, RAR{gamma} knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RAR{gamma} down-regulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RAR{gamma} expression and function Capture of the miR-96 targetome by biotin-miR96 identified that RAR{gamma} and a number of RAR{gamma} interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RAR{gamma} target genes (e.g. SOX15) that significantly associated with worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets a RAR{gamma} network to govern AR signaling, PCa progression and disease outcome.\n\nConflict of interestThe authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.\n\nFUNDINGLESC acknowledges support, in part, of Roswell Park Comprehensive Cancer Center-University of Pittsburg Cancer Institute Ovarian Cancer Specialized Program of Research Excellence National Institutes of Health [P50CA159981-01A1].\n\nMDL acknowledges support of Molecular Pharmacology and Experimental Therapeutics NRSA T32 program [T32CA009072] held at Roswell Park Comprehensive Cancer Center.\n\nMJC and DJS acknowledges support in part from the Prostate program of the Department of Defense Congressionally Directed Medical Research Programs [W81XWH-14-1-0608, W81XWH-11-2-0033] and the National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Centers Genomic Shared Resource.\n\nMJC, GL, AR, HW and PvdB acknowledges support from the European Union-United States Atlantis Program [P116J090011].\n\nMJC and LESC acknowledge support from the National Cancer Institute (NCI) grant P30CA016056 involving the use of OSUCCC The James, CCSG P30CA016058

cancer biology↗