scholarly journals Stress signaling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa

2021 ◽  
Author(s):  
VG Frings ◽  
L Jopp ◽  
M Srivastava ◽  
D Presser ◽  
M Goebeler ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Rna Sequencing ◽  
Expression Pattern ◽  
Hidradenitis Suppurativa ◽  
Gene Expression Pattern ◽  
Epidermal Keratinocytes ◽  
Stress Signaling ◽  
Promising Therapeutic Approach

ABSTRACTBackgroundThe underlying pathogenetic factors generating the innate immune signal necessary for T cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that defective keratinocyte function critically contributes to HS disease development and progression.ObjectivesTo elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of isolated lesional and perilesional HS epidermis by RNA sequencing.MethodsLesional and perilesional HS skin samples of at least 3 different donors were obtained. Isolated epidermal keratinocytes were further processed for cell culture, protein extraction, immunostaining procedures or RNA isolation and RNA sequencing. For large scale promotor site analysis, DEGs were analyzed for overrepresented transcription factor binding sites. Functional annotation clustering for analyzing enriched functional-related gene groups was performed employing the DAVID Bioinformatics Resources.ResultsWe show that HS is characterized by a strong epidermal stress state as evident by a significant overrepresentation of an AP-1-driven stress signature in the overall gene expression pattern of lesional keratinocytes and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional HS epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFNγ production and governs the expression of key inflammatory genes that coordinate activation of innate immunity and the adaptive T cell response in HS.ConclusionsTaken together, these data implicate a new role of combined stress signaling and JAK/STAT1 pathway activation in disease progression of HS suggesting interference with JAK/STAT1 signaling as a potentially promising therapeutic approach for HS.

scholarly journals HOXC4, HOXC5, and HOXC6 Expression in Non-Hodgkin's Lymphoma: Preferential Expression of the HOXC5 Gene in Primary Cutaneous Anaplastic T-Cell and Oro-Gastrointestinal Tract Mucosa-Associated B-Cell Lymphomas

Blood ◽  
1997 ◽  
Vol 90 (10) ◽  
pp. 4116-4125 ◽  
Author(s):  
Janet J. Bijl ◽  
Johan W. van Oostveen ◽  
Jan M.M. Walboomers ◽  
Anja Horstman ◽  
Adriaan J.C. van den Brule ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
B Cell ◽  
Expression Pattern ◽  
Gene Expression Pattern ◽  
Lymphoid Cells ◽  
B Cell Lymphomas ◽  
Preferential Expression ◽  
T Cell Lymphomas ◽  
Hodgkin's Lymphomas

Abstract Most of the 39 members of the homeobox (HOX) gene family are believed to control blood cell development. HOXC4 and HOXC6 gene expression levels increase with differentiation of lymphoid cells. In contrast, HOXC5 is not expressed in the lymphoid lineage, but was found in lymphoid cell lines, representing the neoplastic equivalents of various differentiation stages of T and B lymphocytes. In the present study, we investigated the HOXC4, HOXC5, and HOXC6 gene expression pattern in 89 non-Hodgkin's lymphomas (NHLs) of different histologic subtypes and originating from different sites. Using RNA in situ hybridization and semiquantitative reverse transcription-polymerase chain reaction, we found expression of HOXC4 in 83 of 88 and HOXC6 in 77 of 88 NHLs and leukemias investigated. In contrast, HOXC5 expression was found in only 26 of 87 NHLs and appeared to be preferentially expressed by two specific subsets of lymphomas, ie, primary cutaneous anaplastic T-cell lymphomas (9 of 9) and extranodal marginal zone B-cell lymphomas (maltomas; 7 of 9). These results indicate that, in contrast to HOXC4 and HOXC6, HOXC5 shows a type- and site-restricted expression pattern in both T- and B-cell NHLs.

scholarly journals Gene expression profiling identifies FLT3 mutation-like cases in wild-type FLT3 acute myeloid leukemia

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247093
Author(s):  
Adrián Mosquera Orgueira ◽  
Andrés Peleteiro Raíndo ◽  
Miguel Cid López ◽  
Beatriz Antelo Rodríguez ◽  
José Ángel Díaz Arias ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Pattern ◽  
Gene Expression Pattern ◽  
Wild Type ◽  
Wilcoxon Rank Sum Test ◽  
Recurrent Mutations ◽  
Flt3 Inhibitors ◽  
Predictive Role ◽  
Acute Myeloid

Background FLT3 mutation is present in 25–30% of all acute myeloid leukemias (AML), and it is associated with adverse outcome. FLT3 inhibitors have shown improved survival results in AML both as upfront treatment and in relapsed/refractory disease. Curiously, a variable proportion of wild-type FLT3 patients also responded to these drugs. Methods We analyzed 6 different transcriptomic datasets of AML cases. Differential expression between mutated and wild-type FLT3 AMLs was performed with the Wilcoxon-rank sum test. Hierarchical clustering was used to identify FLT3-mutation like AMLs. Finally, enrichment in recurrent mutations was performed with the Fisher’s test. Results A FLT3 mutation-like gene expression pattern was identified among wild-type FLT3 AMLs. This pattern was highly enriched in NPM1 and DNMT3A mutants, and particularly in combined NPM1/DNMT3A mutants. Conclusions We identified a FLT3 mutation-like gene expression pattern in AML which was highly enriched in NPM1 and DNMT3A mutations. Future analysis about the predictive role of this biomarker among wild-type FLT3 patients treated with FLT3 inhibitors is envisaged.

scholarly journals Sphingolipid Metabolic Pathway: An Overview of Major Roles Played in Human Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Raghavendra Pralhada Rao ◽  
Nanditha Vaidyanathan ◽  
Mathiyazhagan Rengasamy ◽  
Anup Mammen Oommen ◽  
Neeti Somaiya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Expression Pattern ◽  
Metabolic Pathway ◽  
Membrane Lipids ◽  
Gene Expression Pattern ◽  
Bioactive Molecules ◽  
Cellular Processes ◽  
Key Players

Sphingolipids, a family of membrane lipids, are bioactive molecules that participate in diverse functions controlling fundamental cellular processes such as cell division, differentiation, and cell death. Given that most of these cellular processes form the basis for several pathologies, it is not surprising that sphingolipids are key players in several pathological processes. This review discusses the role of the sphingolipid metabolic pathway in diabetes, Alzheimer’s disease, and hepatocellular carcinoma, with a special emphasis on the changes in gene expression pattern in these disease conditions. For convenience, the sphingolipid metabolic pathway is divided into hypothetical compartments (modules) with each compartment representing a physiological process and changes in gene expression pattern are mapped to each of these modules. It appears that alterations in the gene expression pattern in these disease conditions are biased to manipulate the system in order to result in a particular disease.

Abstract 14620: LncExACT1 Acts as a Pivotal Switch Between Physiological and Pathological Cardiac Growth

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Haobo Li ◽  
Lena E Trager ◽  
Xiaojun Liu ◽  
Margaret H Hastings ◽  
CHUNYANG XIAO ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Pattern ◽  
Cardiac Development ◽  
Wheel Running ◽  
Gene Expression Pattern ◽  
Beneficial Effects ◽  
Pathological Hypertrophy ◽  
Physiological Hypertrophy ◽  
Fractional Shortening

Rationale: Pathological hypertrophy commonly leads to heart failure (HF) and loss of cardiomyocytes, while physiological hypertrophy protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain unclear. While long noncoding RNAs (lncRNAs) are important in cardiac development and disease, their role in physiological hypertrophy is unknown. Objective: To investigate the role of lncRNAs in physiological hypertrophy. Methods and Results: Mice underwent voluntary wheel running for eight weeks or transverse aortic constriction (TAC) for two or ten weeks. RNAseq identified a novel set of lncRNAs altered in exercised hearts, which we termed l ong n on c oding Ex ercise- A ssociated C ardiac T ranscripts (lncExACTs). lncExACT1 was highly conserved and uniquely downregulated in exercised hearts but upregulated in pathological animal models and hearts from HF patients vs controls (1.8-fold; p <0.001, N=24) as well as plasma from HF patients with reduced (2.9-fold; p =0.032, N=16) and preserved ejection fraction (3.4-fold; p =0.006, N=18). In mice, AAV9 lncExACT1 overexpression increased cardiac lncExACT1 7-fold at 16 weeks and increased heart (HW) and lung (LW) weight relative to tibial length (TL), reduced fractional shortening (FS) and increased relative wall thickness (RWT) ( p <0.05 for all). These changes were associated with a pathological gene expression pattern. In contrast, antisense lncExACT1 inhibition reduced cardiac expression 2-fold at 2 weeks and increased HW/TL without an increase in LW/TL, improved cardiac function, and increased RWT ( p <0.05 for all). LncExACT1 inhibition induced a physiological gene expression pattern and increased markers of cardiomyogenesis. LncExACT1 inhibition reduced TAC-induced HW/TL and fibrosis, while increasing FS ( p <0.05 for all). Mechanistic studies revealed that lncExACT1 works by binding miR-222 and as a novel regulator of Hippo/Yap1 signaling through modulation of dachsous cadherin-related 2. Conclusions: lncExACT1 acts as a master switch toggling the heart between physiological and pathological growth and provides a potentially tractable therapeutic target for harnessing the beneficial effects of exercise.

scholarly journals The Role of NKL Homeobox Genes in T-Cell Malignancies

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1676
Author(s):  
Stefan Nagel
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Gene Expression Pattern ◽  
Homeobox Genes ◽  
The Other ◽  
Hematopoietic Malignancies ◽  
Normal Functions ◽  
T Cell Malignancies

Homeobox genes encode transcription factors controlling basic developmental processes. The homeodomain is encoded by the homeobox and mediates sequence-specific DNA binding and interaction with cofactors, thus operating as a basic regulatory platform. Similarities in their homeobox sequences serve to arrange these genes in classes and subclasses, including NKL homeobox genes. In accordance with their normal functions, deregulated homeobox genes contribute to carcinogenesis along with hematopoietic malignancies. We have recently described the physiological expression of eleven NKL homeobox genes in the course of hematopoiesis and termed this gene expression pattern NKL-code. Due to the developmental impact of NKL homeobox genes these data suggest a key role for their activity in the normal regulation of hematopoietic cell differentiation including T-cells. On the other hand, aberrant overexpression of NKL-code members or ectopical activation of non-code members has been frequently reported in lymphoid and myeloid leukemia/lymphoma, demonstrating their oncogenic impact in the hematopoietic compartment. Here, we provide an overview of the NKL-code in normal hematopoiesis and discuss the oncogenic role of deregulated NKL homeobox genes in T-cell malignancies.

Targeted gene expression classifier identifies pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients at high risk for end induction minimal residual disease positivity.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10002-10002
Author(s):  
Lauren K. Meyer ◽  
Ritu Roy ◽  
Benjamin J. Huang ◽  
Cristina Delgado-Martin ◽  
Tiffaney L. Vincent ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Expression Pattern ◽  
Residual Disease ◽  
Gene Expression Pattern ◽  
Rna Seq ◽  
Gene Expression Classifier ◽  
Minimal Residual

10002 Background: The heterogeneity of T-ALL has hindered biomarker identification and limited biology-based risk stratification. Historically, minimal residual disease (MRD) has been the strongest predictor of poor outcomes. However, stratification by MRD does not allow for risk-adapted therapy early in treatment, which may induce deeper remissions and decrease risk of relapse. We hypothesized that gene expression profiling at diagnosis may have prognostic value in identifying high risk patients. Methods: We analyzed RNA-seq data from 189 diagnostic samples from the Children’s Oncology Group (COG) AALL0434 trial. Using leave-one-out cross-validation, we identified a set of genes that optimally differentiated MRD+ and MRD- samples. We then derived a risk score (RS) that indicates a probability of being MRD+ for a given gene expression pattern. Finally, we validated this model in an independent cohort of COG AALL1231 samples. Results: The AALL0434 early T-cell precursor (ETP) samples (n = 19), which have high rates of MRD+, had the highest RS, with an average of 81.3 (SD 18.7), versus 24.9 (SD 22.7) for non-ETPs (n = 146). Intriguingly, non-ETPs with RS > 50 had a gene expression pattern that mirrored ETPs and was distinct from the remaining non-ETPs. In this RS > 50 non-ETP cohort, 80% were MRD+, versus 20% of the < 50 cohort (p < 0.0001). When applied to 31 diagnostic non-ETP samples from COG AALL1231, 57% of the RS > 50 cohort were MRD+, versus 17% of the RS < 50 cohort (p = 0.05). Importantly, AALL0434 used prednisone during induction, while AALL1231 used dexamethasone, indicating that the predictive value is independent of the induction steroid. Finally, we converted our model to the customizable Nanostring nCounter platform by analyzing 96 AALL0434 samples on the Nanostring assay. The Nanostring data closely recapitulated the RNA-seq data, with a tight correlation between the resulting RS (concordance correlation coefficient = 0.91). Conclusions: We have developed a gene expression classifier that differentiates a subset of non-ETP T-ALLs with an ETP-like gene expression pattern and a high risk of MRD+, and have adapted the classifier to a clinically tractable targeted platform. Identification of this high-risk subset at diagnosis has the potential to facilitate risk-adapted trials to evaluate the utility of novel or more intensive therapies aimed at improving clinical outcomes.

Sign in / Sign up

Export Citation Format

Share Document