In-Vivo Study of Erythropoietic Pathway Genes Regulation and Differentiation by Prolonged Simultaneous Administration of Glucocorticoids with Epoietin in Animal Modules

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4798-4798
Author(s):  
Aref Agheli ◽  
Boris Avezbakiyev ◽  
William Steier ◽  
Madhumati Kalavar ◽  
Chi Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Real Time ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Hemoglobin Concentration ◽  
P Value ◽  
Simultaneous Administration ◽  
Epoetin Alfa ◽  
Rt Pcr ◽  
Gene Expressions

Abstract Abstract 4798 Objectives: The role of steroids in mammalian erythropoiesis has not well defined. We have previously reported our observation on three human cases in which there was a synergism and accelerated response to the Erythropoietic Stimulating Agents (ESA) with simultaneous low and physiologic dose administration of glucocorticoids. In the current study, we investigated the additive effects of different dose schedules of steroids on hematopoietic effects of ESA in animal modules. Methods: A total of 74, four-weeks old male Sprague-Dawley rats were randomized to 6 groups; (A) control, (B) therapeutic doses of either erythropoietin, [Procrit Epoetin Alfa, 100 UI/kg], or (C) dexamethasome (300 mcg/kg), as well as combination of erythropoietin (Epoetin Alfa, 100 UI/kg) with (D) low, [25 mcg/kg], (E) physiologic, [300 mcg/kg], and (F) high, [2.5 mg/kg] doses of dexamethasone through abdominal hypodermal injection three times a week for a total of four weeks. At the conclusion of the study, peripheral blood sample, and Bone marrow mononuclear cells were collected through femur flushing. The samples were lysed and stored in RNA denaturation buffer at –80°C until use. Expressions of multiple hematopoietic major genes were assessed by real-time RT-PCR. Amplification data were processed using ΔΔCt method. Hemoglobin concentration and other CBC parameters were measured at the reference lab. Results: Mean hemoglobin concentrations were significantly higher in groups D (20.76 g/dl, 95% CI 20.08–21.45), E (20.45 g/dl, 95% CI, 19.97–20.94), and F (20.99 g/dl, 95% CI 20.55–21.42), compared to the controlled groups A, B, C (14.57, 15.68, 19.23 g/dl respectively) with two-tailed p-value of <.0001. (Figure-1) Real time RT-PCR based gene expression profiling of major hematopoietic regulators revealed robot increases of JAK2 gene expression in groups of animals treated with EPO only, or even higher increase with EPO plus either low or physiologic doses of dexamethasome. Similarly, GATA-1 levels are increased in groups treated with EPO only, or EPO with low or physiologic doses of dexamethasome. c-kit and NFkB1 expression levels are markedly higher in EPO plus dexamethasome groups. In contrast, the levels of EPOR are generally reduced in all groups receiving ESA. (Figure -2) Conclusion: The findings in this study is suggestive that simultaneous administration of ESAs with glucocorticoids is associated with significant additive elevation of the hemoglobin concentration; however, higher dose of dexamethasone is associated with more frequent adverse side effects such as significant weight loss. It is also suggested that the erythropoietic effect of steroid is concerted by up-regulation of the multiple erythropoietic gene expressions, such as JAK2, GATA-1, c-Kit, and NFkB1, while down regulations of EPOR is uniformly seen in the Epo-treated groups. This novel finding could be clinically utilized to accelerate the erythropoietic response of the ESA in selected cases. Disclosures: No relevant conflicts of interest to declare.

The Alteration of SEPT5 Gene Expression in BCR-ABL Positive Cells and Its Possible Correlation with the Development and / or Progression of Chronic Myeloid Leukemia (CML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4415-4415
Author(s):  
Cintia Do Couto Mascarenhas ◽  
Anderson Ferreira Cunha ◽  
Ana Flavia Brugnerotto ◽  
Sheley Gambero ◽  
Joao Machado-Neto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Real Time ◽  
Cell Lines ◽  
Real Time Pcr ◽  
Blood Donors ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Blood Platelets ◽  
Gene Expression Pattern ◽  
P Value

Abstract Abstract 4415 The CML is a clonal disease of stem cells and its main feature is the unregulated production of a tyrosine kinase protein called BCR-ABL, the progression of the disease to accelerated phase or blast crisis may be associated with genomic instability. Because of this, the use of tools for the study of gene expression could bring new insights in the understanding of these mechanisms in the CML. In a recent study using SSH libraries, we compared the gene expression pattern between granulocytes of health control and CML patients, and we identified the gene SEPT5 expressed only in CML patients. Although the studies in the literature, there is not a clear relationship between the expression of this gene and the development or progression of CML. SEPT5 is a member of nucleotide binding proteins called septins that were firstly described in yeast as cell division cycle regulatory proteins. This gene was reported in patients with AML translocated with MLL gene, in adult human brain and heart; it is also associated with alpha granules of human blood platelets. The aims of this study are to carry a functional analysis of SEPT5 in differents cells line and to study the relationship of this gene and the development and/or progression of CML. The gene expression evaluation was made in granulocytes, mononuclear cells and total leukocytes of CML patients and healthy blood donors in peripheral blood. It was also evaluated in bone marrow donors, in human cell lines (K562, HL60 and NB4) and in mice cell lines (BaF3/BCR-ABLp210 and BaF3T315I), performed by real-time PCR for the following genes: SEPT5, β-actin and GAPDH. Experiments were also performed to verify the difference between the chemotaxis of granulocytic cells from controls and patients by ELISA. Data were analysed statistically using the ANOVA followed by Dunnett’s test – P value of less than 0.05 was considered to be significant. The study was approved by the Research Ethic Committee of the Faculty of Medical Sciences of University of Campinas. The gene expression of SEPT5 was evaluated by real time PCR using the same samples used in the library construction to validate the results found in the SSH library. The data confirmed our previous results, showing that the SEPT5 expression is increased in all cells of patients compared to controls. The same results were observed when we studied the expression comparing individually patients and health blood donors, suggesting that this protein could be increased in all human cells that present the translocation BCR-ABL. The level of expression of this gene in HL60 and NB4 was significantly lower than in K562 cell line. The experiments with mice cell lines showed a higher expression of this gene in BaF3T315I when compared to BaF3BCR-ABLp210. We obtained a significant expression difference in all experiments (p <0.05). The spontaneous and stimulated with IL-8 chemotaxis assays used granulocytes and were assessed using chamber containing 96 wells. However, although the results suggest an increased chemotactic activity in patients, there were no significant differences (p<0.05) between controls and patients – regardless of whether the chemotaxis was spontaneous or stimulated with IL-8. In mammals the SEPT5 gene is associated with cellular processes such as exocytosis, apoptosis, leukemogenesis, carcinogenesis and neurodegeneration. Therefore, molecules capable of interacting with the septins, either at biochemical or molecular level, can bring information about their functions in cytokinesis. Studies indicate that the human septins can interact among themselves and with other components of the cytoskeleton – this may be a relevant observation regarding the function of this gene in cancer. The SEPT5 can be activated by different pathways – this may increase expression in translocated cells. Despite major advances in the treatment of CML, the treatments available are not capable of inactivating all the signaling pathways activated by BCR/ABL. Our results demonstrate that SEPT5 may be involved in the pathophysiology of CML. Also, it is clear the importance of the study of pathways that could culminate in its high expression or the triggering of other unknown pathways involved in the development of CML. The increased expression of this gene may be related to disease progression, and finally, the identification of several important genes may lead to a better understanding of CML and helping to identify new therapeutic targets. FAPESP/INCT. Disclosures: No relevant conflicts of interest to declare.

Transcriptosome Profiling of B-CLL Identifies WNT-3A and ROR-1 as an Autocrine Mechanism in Cell Survival.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2116-2116
Author(s):  
James Choi ◽  
B. Simons ◽  
Chris Riley ◽  
T. Klinkhammer ◽  
Laurence Cooke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Real Time ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Western World ◽  
Specific Gene ◽  
Rt Pcr ◽  
Normal Peripheral Blood

Abstract Background: B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia afflicting the Western world. B-CLL accounts for 25% of all newly diagnosed leukemias. Despite many new therapeutic advances, B-CLL is still not a curable malignancy. The hallmark feature is the presence of an elevated number of circulating clonal leukemic B cells that typically express CD 5, CD 19, CD 23, and low levels of surface immunoglobulins. Methods: Mononuclear cells from 5 patients were analyzed utilizing the HG-U133A 2.0 Affymetrix array (~18,400 transcripts, 22,000 probe sets) after isolating and purifying total RNA (Qiagen, RNAeasy). The control RNA samples were isolated from normal peripheral blood (PB) B-cell (AllCell, CA). Immunohistochemistry (IHC) confirmed tumor lineage and quantitative real time RT-PCR was performed on selected genes to validate the microarray study. The GEP data was processed and analyzed utilizing Affymetrix MAS 5.0 and GeneSpring 5.0 software. Our data was analyzed in the light of published GEP of B-cell CLL. Fifteen B-CLL patients (retrospectively) were evaluated by RT-PCR for ROR-1 and WNT-3A with gene specific probes. As a potential therapy, thalidomide was evaluated on B-CLL cells grown in cell culture for 24 hours. GEP of the thalidomide treated B-CLL from the initial 5 patients was performed to look for gene expression changes that could drive the B-CLL toward apoptosis. A homology model of ROR-1 tyrosine kinase was built, ATP docked and in silico databases screened for potential lead molecules. Results: Data are represented as “robust” increases or decreases of relative gene expression common in the 5 patients. However, ROR-1 and WNT-3A were consistently over-expressed together in these 5 patients. The average increase was 25-fold for ROR-1 and 7-fold by WNT-3A when compared to normal B-cell RNA. Of the 15 patients we evaluated for ROR-1 and WNT-3A with gene specific probes, the increase in gene expression correlated well with our initial gene expression profiling study. Thalidomide specific gene changes included several molecules involved in apoptosis. Of these gene changes, Bcl-G, p35, and Cdk-5 were up-regulated several fold. Data will be presented on the influence of the stage of disease on ROR-1 and WNT-3A expression. Conclusions: GEP of B-CLL in combination with quantitative real time RT-PCR has identified several novel therapeutic targets for therapy based on a comparison to normal (B-cell) RNA. GEP has identified ROR-1 as a key component in an autocrine pathway that helps B-CLL elude apoptosis. The identification of this novel tyrosine kinase-like protein has led to the development of a molecular target for future therapeutic applications. Several lead compounds have been identified and are being evaluated as potential therapeutics in B-CLL.

scholarly journals RNA-Based Drug Screening Using Automated RNA Purification and Real-time RT-PCR1

2004 ◽  
Vol 9 (2) ◽  
pp. 95-102 ◽  
Author(s):  
Susanne Ullmann ◽  
Thorsten Hage ◽  
Regina Draheim ◽  
Ute Egerland ◽  
Uwe OelmÜller ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Real Time ◽  
Drug Screening ◽  
Mononuclear Cells ◽  
Assay System ◽  
Automated System ◽  
Chronic Obstructive ◽  
Rt Pcr ◽  
Rna Purification

A new system has been developed for RNA-based drug screening, and the feasibility of this approach has been demonstrated by the identification of new immunomodulating compounds. Peripheral blood mononuclear cells were chosen as the cellular assay system. Cells were either stimulated by TPA/ionomycin to produce T cell cytokines as asthma targets or stimulated by lipopolysaccharide to produce proinflammatory cytokines as targets for chronic obstructive pulmonary disease (COPD). The authors developed a new fully automated system for RNA purification from cells grown in 96-well plates. Gene expression was determined in 384-well plates using real-time quantitative one-tube RT-PCR. Small interdonor variation could be demonstrated. The assay system was validated with known immunosuppressants cyclosporine and dexamethasone. Screening of 800 compounds resulted in 9.5% compounds inhibiting the induction of at least 1 T cell derived cytokine and 6.8% compounds inhibiting at least 1 cytokine relevant for COPD. All these compounds were retested by analyzing remaining RNA from the 1st round of screening. The reproducibility of hits was between 56% and 74% for different cytokines. One compound selectively inhibited TNF, which was confirmed by IC50 determination. Analyzing its effect on cells from different donors revealed little interdonor variation. In conclusion, the authors established fully automated RNA isolation and precise gene expression profiling using real-time RT-PCR for drug screening. ( Journal of Biomolecular Screening 2004:95-102)

Research of Gene Expression in Patients with Myelodysplastic Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4433-4433
Author(s):  
Bao-An Chen ◽  
Bo Zhang ◽  
Chong Gao ◽  
Guo-Hua Xia ◽  
Ze-ye Shao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Clinical Significance ◽  
Myelodysplastic Syndromes ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Bone Marrow Mononuclear Cells ◽  
Rt Pcr ◽  
Normal People ◽  
Significant Difference

Abstract Abstract 4433 Object This study was aimed to investigate the expression of c-FLIPL, c-FLIPS and DLK1 mRNA in Myelodysplastic Syndromes (MDS) patients, as compared with normal people and AML patients, and to find its clinical significance. Methods The expression of c-FLIPL, c-FLIPS and DLK1 mRNA in bone marrow mononuclear cells (BMNNC) of 16 patients with MDS, 8 patients with AML and 3 controls were detected by RT-PCR. Results The expression of DLK1 mRNA was up-regulated in MDS, including RA and RAEB, as compared with controls(P<0.05). There was no significant difference in expression of DLK1 between RA and RAEB(P>0.05). The expression of DLK1 was significant higher in AML patients, compared with controls(P<0.05). There was no significant difference between MDS and AML patients(P>0.05). The expression of c-FLIPL mRNA was higher than that in controls, both in RA and RAEB(P<0.05). There was no significant difference in expression of c-FLIPL between RA and RAEB(P>0.05). In eight AML patients, c-FLIPL gene's expression was up-regulated, as compared with controls(P<0.05). Between AML and MDS patients, there was no significant difference(P>0.05); The expression of c-FLIPS mRNA had no significant difference between MDS patients and controls(P>0.05), but its expression in RAEB was significant higher as compared with RA patients and controls(P<0.05). And in AML patients, the expression of c-FLIPS was higher than that in controls(P<0.05), but there was no significant difference between AML and MDS patients(P>0.05). Conclusion It is concluded that the expressions of DLK1, c-FLIPL and c-FLIPS mRNA in MDS/AML patients are abnormal as compared with normal people, although there are no significant difference have been found between AML and MDS. These genes may play critical roles in escaping malignant clone of MDS from apoptosis and acquiring the ability to divide unlimitedly, they can become important indexes for evaluating of development in MDS. Disclosures: No relevant conflicts of interest to declare.

The Protective Effect of Metformin against Oxandrolone-Induced Infertility in Male Rats

2020 ◽  
Vol 26 ◽  
Author(s):  
Abdulqader Fadhil Abed ◽  
Yazun Bashir Jarrar ◽  
Hamzeh J Al-Ameer ◽  
Wajdy Al-Awaida ◽  
Su-Jun Lee
Keyword(s):  
Gene Expression ◽  
Male Infertility ◽  
Protective Effect ◽  
Histological Examination ◽  
Sperm Count ◽  
Serum Testosterone ◽  
Male Rats ◽  
P Value ◽  
Protective Effects ◽  
Rt Pcr

Background: Oxandrolone is a synthetic testosterone analogue that is widely used among bodybuilders and athletes. However, oxandrolone causes male infertility. Recently, it was found that metformin reduces the risk of infertility associated with diabetes mellitus. Aim: This study aimed to investigate the protective effects of metformin against oxandrolone-induced infertility in male rats. Methods: Rats continuously received one of four treatments (n=7) over 14 days: control DMSO administration, oxandrolone administration, metformin administration, or co-administration of oxandrolone and metformin. Doses were equivalent to those used for human treatment. Subsequently, testicular and blood samples were collected for morphological, biochemical, and histological examination. In addition, gene expression of the testosterone synthesizing enzyme CYP11A1 was analyzed in the testes using RT-PCR. Results: Oxandrolone administration induced male infertility by significantly reducing relative weights of testes by 48%, sperm count by 82%, and serum testosterone levels by 96% (ANOVA, P value < 0.05). In addition, histological examination determined that oxandrolone caused spermatogenic arrest which was associated with 2-fold downregulation of testicular CYP11A1 gene expression. However, co-administration of metformin with oxandrolone significantly ameliorated toxicological alterations induced by oxandrolone exposure (ANOVA, P value < 0.05). Conclusion: Metformin administration protected against oxandrolone-induced infertility in male rats. Further clinical studies are needed to confirm the protective effect of metformin against oxandrolone-induced infertility among athletes.

scholarly journals Human mononuclear cells express 12-LX: coordinated mRNA regulation with 5-LX and FLAP genes

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 331-340
Author(s):  
WE Kaminski ◽  
E Jendraschak ◽  
K Baumann ◽  
R Kiefl ◽  
S Fischer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Time Course ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Constitutive Expression ◽  
Ionophore A23187 ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Human Mononuclear Cells

Lipoxygenases (LXs) catalyze formation of leukotrienes and hydroxy-eicosatetraenoic acids (HETEs), proinflammatory, and spasmogenic autacoids that are critical for host defense systems. We studied the expression and regulation of LX genes (12-LX, 5-LX, and 15-LX) and the 5-lipoxygenase activating protein (FLAP) in human mononuclear cells (MNC) and granulocytes using a quantitative reverse transcription polymerase chain reaction (RT-PCR) technique. We show that 12-LX mRNA is constitutively expressed in resting platelet-free MNC. 12-LX gene expression was upregulated by activation with lipopolysaccharide (LPS). The formation of 12-HETE was inducible with ionophore in MNC, as assessed by high-performance liquid chromatography (HPLC) and gas chromatography, and increased after LPS pretreatment. In addition to 12- LX, resting MNC expressed the genes for 5-LX and FLAP constitutively. Quantitative time course analyses of 12-LX, 5-LX, and FLAP gene expression suggested coregulation of 12-LX and FLAP mRNAs, and reciprocal regulation of 5-LX and FLAP mRNAs. During cell stimulation with LPS 5-LX mRNA levels remained unchanged, whereas FLAP gene expression increased. No 15-LX mRNA expression or 15-HETE formation was detectable in unstimulated and activated MNC. In contrast to MNC, quantitative RT-PCR mRNA analysis showed intermittent intraindividual expression of the 5-LX and FLAP genes in resting granulocytes. mRNAs for 12-LX and 15-LX were not expressed. On stimulation of granulocytes ex vivo, mRNA expression of 5-LX and FLAP was upregulated. Stimulation by LPS differed from that by ionophore A23187. Neither LPS nor ionophore induced gene expression of 12-LX or 15-LX in granulocytes. Our data indicate that resting human MNC and granulocytes express LX and FLAP genes in a cell-specific manner. Cell activation induces coordinated upregulation of 12-LX and FLAP genes in MNC, and 5-LX and FLAP genes in granulocytes, respectively. The constitutive expression of 12-LX mRNA, its upregulation on cell activation, and the formation of 12-HETE clearly indicate the presence of a functional 12-LX in human MNC.

scholarly journals TLR, RAGE, and HMGB1 in the Inflammatory Response in Ph(-) Myeloproliferative Neoplasm

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Guanfang Shi ◽  
Kiron Nair ◽  
Preethi Ramachandran ◽  
Chi Chen ◽  
Ching Wong ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Real Time ◽  
Inflammatory Cytokines ◽  
Internal Control ◽  
Real Time Pcr ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Significant Difference

Recent evidence of increased constitutional symptoms and inflammatory cytokines in Philadelphia chromosome negative (Ph (-)) MPN suggests that an inflammatory response is important in the pathogenesis of Ph (-) MPN. Toll-like receptors (TLR), Receptor for Advanced Glycation End products (RAGE) and High mobility group protein B1 (HMGB1) are the important pathways for the inflammatory response. All these three important pathway proteins were studied in MPN diseases in the current studies. Materials and Methods: TLR assay. TLR 2,3, 4, 7, 9 quantification was performed by immuno-staining of 1×106 mononuclear cells (peripheral blood) which were incubated with fluorescence-conjugated anti-TLR-2,3, 4, 7, 9 antibodies and assayed by flow cytometry. HMGB1assay:HMGB1 ELISA kit from Immuno-Biological Laboratories, Inc. (IBL-America) were used. The plasma samples were diluted four times with the provided sample dilution buffer, and assayed in duplicate according to the manufacturer's suggestion. RAGE (RT-PCR) Assay: Total RNA was extracted from normal control or patient mononuclear cells. Predesigned primers for RAGE, and internal control genes were ordered from Qiagen (Germantown, MD). Real-time PCR was performed using SsoAdvanced™ Universal SYBR® Green Supermix (Bio-Rad, Hercules, CA) on Bio-Rad iQ5 Multicolor Real-Time PCR Detection System. At least three house-keeping genes (ribosomal protein L4, TATA box binding protein, and tubulin-α 1b) were used as normalization controls. The expression of RAGE were compared with each internal control. Average of three was used to calculate the ratio of final patient to normal Results: Total of 97 patients with MPN were studied 1) TLR: TLR 3,7,9 was not significantly different from controls. But TLR 2 was significantly increased in both PV, as well as in the MPN group when PV, ET and MF were grouped together as MPN (Fig A). TLR 4 was not significantly increased in PV, ET, MF individually but was found to be significantly increased than the controls, when they are grouped together as MPN (Fig B). 2) RAGE: No significant difference was found between ET, PV, MF individually or when they were grouped together as MPN than the controls (Fig C). 3) HMGB1: No significant difference was seen between ET, PV, MF or when they were grouped as MPN (Fig D). Conclusion: Current study suggests that TLR pathway especially TLR2, and to a lesser extent TLR4 are the important pathways for inflammatory response with increased inflammatory cytokines in MPN, while HMGB1 and RAGE pathways were not different from controls. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Dysregulation of MS risk genes and pathways at distinct stages of disease

2017 ◽  
Vol 4 (3) ◽  
pp. e337 ◽  
Author(s):  
Sundararajan Srinivasan ◽  
Marco Di Dario ◽  
Alessandra Russo ◽  
Ramesh Menon ◽  
Elena Brini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Gene List ◽  
Literature Mining ◽  
Specific Gene ◽  
Healthy Population ◽  
Gene Expressions ◽  
Altered Expression ◽  
Risk Genes

Objective:To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions.Methods:We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining.Results:Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage–specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS.Conclusions:Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways.

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