scholarly journals Comparative Gene Expression Analysis Reveals Similarities and Differences of Chronic Myeloid Leukemia Phases

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 256
Author(s):  
Annemarie Schwarz ◽  
Ingo Roeder ◽  
Michael Seifert
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Signaling Pathway ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Chronic Phase ◽  
Receptor Interaction ◽  
Similarities And Differences

Chronic myeloid leukemia (CML) is a slowly progressing blood cancer that primarily affects elderly people. Without successful treatment, CML progressively develops from the chronic phase through the accelerated phase to the blast crisis, and ultimately to death. Nowadays, the availability of targeted tyrosine kinase inhibitor (TKI) therapies has led to long-term disease control for the vast majority of patients. Nevertheless, there are still patients that do not respond well enough to TKI therapies and available targeted therapies are also less efficient for patients in accelerated phase or blast crises. Thus, a more detailed characterization of molecular alterations that distinguish the different CML phases is still very important. We performed an in-depth bioinformatics analysis of publicly available gene expression profiles of the three CML phases. Pairwise comparisons revealed many differentially expressed genes that formed a characteristic gene expression signature, which clearly distinguished the three CML phases. Signaling pathway expression patterns were very similar between the three phases but differed strongly in the number of affected genes, which increased with the phase. Still, significant alterations of MAPK, VEGF, PI3K-Akt, adherens junction and cytokine receptor interaction signaling distinguished specific phases. Our study also suggests that one can consider the phase-wise CML development as a three rather than a two-step process. This is in accordance with the phase-specific expression behavior of 24 potential major regulators that we predicted by a network-based approach. Several of these genes are known to be involved in the accumulation of additional mutations, alterations of immune responses, deregulation of signaling pathways or may have an impact on treatment response and survival. Importantly, some of these genes have already been reported in relation to CML (e.g., AURKB, AZU1, HLA-B, HLA-DMB, PF4) and others have been found to play important roles in different leukemias (e.g., CDCA3, RPL18A, PRG3, TLX3). In addition, increased expression of BCL2 in the accelerated and blast phase indicates that venetoclax could be a potential treatment option. Moreover, a characteristic signaling pathway signature with increased expression of cytokine and ECM receptor interaction pathway genes distinguished imatinib-resistant patients from each individual CML phase. Overall, our comparative analysis contributes to an in-depth molecular characterization of similarities and differences of the CML phases and provides hints for the identification of patients that may not profit from an imatinib therapy, which could support the development of additional treatment strategies.

Diagnosing and Managing Advanced Chronic Myeloid Leukemia

2015 ◽  
pp. e381-e388 ◽  
Author(s):  
Michael W. Deininger
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Chronic Phase ◽  
Clinical Staging ◽  
Molecular Monitoring ◽  
Hematopoietic Stem

Clinical staging of chronic myeloid leukemia (CML) distinguishes between chronic phase (CP-CML), accelerated phase (AP-CML), and blastic phase (BP-CML), reflecting its natural history in the absence of effective therapy. Morphologically, transformation from CP-CML to AP/BP-CML is characterized by a progressive or sudden loss of differentiation. Multiple different somatic mutations have been implicated in transformation from CP-CML to AP/BC-CML, but no characteristic mutation or combination of mutations have emerged. Gene expression profiles of AP-CML and BP-CML are similar, consistent with biphasic evolution at the molecular level. Gene expression of tyrosine kinase inhibitor (TKI)–resistant CP-CML and second CP-CML resemble AP/BP-CML, suggesting that morphology alone is a poor predictor of biologic behavior. At the clinical level, progression to AP/BP-CML or resistance to first-line TKI therapy distinguishes a good risk condition with survival close to the general population from a disease likely to reduce survival. Progression while receiving TKI therapy is frequently caused by mutations in the target kinase BCR-ABL1, but progression may occur in the absence of explanatory BCR-ABL1 mutations, suggesting involvement of alternative pathways. Identifying patients in whom milestones of TKI response fail to occur or whose disease progress while receiving therapy requires appropriate molecular monitoring. Selection of salvage TKI depends on prior TKI history, comorbidities, and BCR-ABL1 mutation status. Despite the introduction of novel TKIs, therapy of AP/BP-CML remains challenging and requires accepting modalities with substantial toxicity, such as hematopoietic stem cell transplantation (HSCT).

scholarly journals Characterization of Embryonic Skin Transcriptome in Anser cygnoides at Three Feather Follicles Developmental Stages

2019 ◽  
Vol 10 (2) ◽  
pp. 443-454
Author(s):  
Chang Liu ◽  
Cornelius Tlotliso Sello ◽  
Yujian Sui ◽  
Jingtao Hu ◽  
Shaokang Chen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Developmental Stages ◽  
De Novo ◽  
Transcriptome Assembly ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Mitogen Activated Protein Kinase ◽  
Receptor Interaction ◽  
Keratinocyte Proliferation ◽  
Skin Development

In order to enrich the Anser cygnoides genome and identify the gene expression profiles of primary and secondary feather follicles development, de novo transcriptome assembly of skin tissues was established by analyzing three developmental stages at embryonic day 14, 18, and 28 (E14, E18, E28). Sequencing output generated 436,730,608 clean reads from nine libraries and de novo assembled into 56,301 unigenes. There were 2,298, 9,423 and 12,559 unigenes showing differential expression in three stages respectively. Furthermore, differentially expressed genes (DEGs) were functionally classified according to genes ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and series-cluster analysis. Relevant specific GO terms such as epithelium development, regulation of keratinocyte proliferation, morphogenesis of an epithelium were identified. In all, 15,144 DEGs were clustered into eight profiles with distinct expression patterns and 2,424 DEGs were assigned to 198 KEGG pathways. Skin development related pathways (mitogen-activated protein kinase signaling pathway, extra-cellular matrix -receptor interaction, Wingless-type signaling pathway) and genes (delta like canonical Notch ligand 1, fibroblast growth factor 2, Snail family transcriptional repressor 2, bone morphogenetic protein 6, polo like kinase 1) were identified, and eight DEGs were selected to verify the reliability of transcriptome results by real-time quantitative PCR. The findings of this study will provide the key insights into the complicated molecular mechanism and breeding techniques underlying the developmental characteristics of skin and feather follicles in Anser cygnoides.

scholarly journals Characterization of the Community Structure of a Dechlorinating Mixed Culture and Comparisons of Gene Expression in Planktonic and Biofloc-Associated “Dehalococcoides” and Methanospirillum Species

2008 ◽  
Vol 74 (21) ◽  
pp. 6709-6719 ◽  
Author(s):  
Annette R. Rowe ◽  
Brendan J. Lazar ◽  
Robert M. Morris ◽  
Ruth E. Richardson
Keyword(s):  
Gene Expression ◽  
16S Rrna ◽  
16S Rrna Gene ◽  
Population Distribution ◽  
Enrichment Culture ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Rrna Gene ◽  
Hydrogenase Gene

ABSTRACT This study sought to characterize bacterial and archaeal populations in a perchloroethene- and butyrate-fed enrichment culture containing hydrogen-consuming “Dehalococcoides ethenogenes” strain 195 and a Methanospirillum hungatei strain. Phylogenetic characterization of this microbial community was done via 16S rRNA gene clone library and gradient gel electrophoresis analyses. Fluorescence in situ hybridization was used to quantify populations of “Dehalococcoides” and Archaea and to examine the colocalization of these two groups within culture bioflocs. A technique for enrichment of planktonic and biofloc-associated biomass was developed and used to assess differences in population distribution and gene expression patterns following provision of substrate. On a per-milliliter-of-culture basis, most D. ethenogenes genes (the hydrogenase gene hupL; the highly expressed gene for an oxidoreductase of unknown function, fdhA; the RNA polymerase subunit gene rpoB; and the 16S rRNA gene) showed no statistical difference in expression between planktonic and biofloc enrichments at either time point studied (1 to 2 and 6 h postfeeding). Normalization of transcripts to ribosome (16S rRNA) levels supported that planktonic and biofloc-associated D. ethenogenes had similar gene expression profiles, with one notable exception; planktonic D. ethenogenes showed higher expression of tceA relative to biofloc-associated cells at 6 h postfeeding. These trends were compared to those for the hydrogen-consuming methanogen in the culture, M. hungatei. The vast majority of M. hungatei cells, ribosomes (16S rRNA), and transcripts of the hydrogenase gene mvrD and the housekeeping gene rpoE were observed in the biofloc enrichments. This suggests that, unlike the comparable activity of D. ethenogenes from both enrichments, planktonic M. hungatei is responsible for only a small fraction of the hydrogenotrophic methanogenesis in this culture.

Enumeration and Immunologic Characterization of Basophils in Normal Bone Marrow and Patients with Myeloproliferative Disorders.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4754-4754
Author(s):  
Hermine Agis ◽  
Maria T. Krauth ◽  
Leonhard Muellauer ◽  
Lawrence B. Schwartz ◽  
Hans P. Horny ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Histidine Decarboxylase ◽  
Chronic Phase ◽  
Myeloproliferative Disorders ◽  
Staining Procedure ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded

Abstract Basophils are highly specialized granulocytes that express a unique profile of antigens and increase in myeloproliferative disorders. In chronic myeloid leukemia (CML), basophilia is an independent prognostic variable. So far, however, no reliable immunohistochemical approach for routine-detection and enumeration of bone marrow (bm) basophils has become available. To overcome this disadvantage, we have applied the anti-basophil antibody 2D7 on formalin-fixed, paraffin-embedded sections of normal bm and bm from patients (pts) with chronic myeloid leukemia (CML; chronic phase, n=21; accelerated phase, n=9), other myeloproliferative disorders (idiopathic myelofibrosis [IMF], n=3; polycythemia vera [PV], n=7; essential thrombocythemia [ET], n=7), and normal / reactive bm (n=32). As assessed by serial section-staining of bm specimens, the 2D7 antibody was found to be a basophil-specific immunohistochemical reagent. In serial bm sections, 2D7+ basophils co-expressed histidine decarboxylase, CD15, and CD43, but did not express B- or T-cell restricted antigens corresponding to the phenotype of normal blood basophils. Bm basophils were found to increase in number in pts with CML and other myeloproliferative disorders compared to normal bm (median 2D7+ cells/mm2 bm: normal bm: 7; CML: 46; IMF: 26; PV: 21; ET: 21, p<.05). The highest numbers of bm basophils were recorded in pts with accelerated phase CML (111 2D7+ cells/mm2). Together, we have established a useful immunohistochemical staining procedure for basophil detection in normal bm and pts with myeloid neoplasms. This approach should enable the quantification of basophils in these pts and the monitoring of bm basophil counts during follow up examinations and anti-leukemic therapies.

Gene expression profiling in bladder cancer to identify potential therapeutic targets.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4518-4518
Author(s):  
Syed A. Hussain ◽  
Daniel H. Palmer ◽  
Wing Kin Syn ◽  
Joseph J Sacco ◽  
Bryony Lloyd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Hierarchical Clustering ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Invasive Cancer ◽  
Classical Complement Pathway ◽  
Grade 3 ◽  
Muscle Invasive

4518 Background: Characterization of gene expression patterns in bladder cancer (BC) allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Methods: Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Results: Hierarchical clustering defined signatures, which differentiated between cancer and normal, muscle-invasive or non-muscle invasive cancer and normal, g1 and g3. Pathways associated with cell cycle and proliferations were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer as compared to normal tissue. Conclusions: This study contributes to a growing body of work on gene expression signatures in BC. The data support an important role for osteopontin in BC, and identify several pathways worthy of further investigation. [Table: see text]

scholarly journals The derivation of diagnostic markers of chronic myeloid leukemia progression from microarray data

Blood ◽  
2009 ◽  
Vol 114 (15) ◽  
pp. 3292-3298 ◽  
Author(s):  
Vivian G. Oehler ◽  
Ka Yee Yeung ◽  
Yongjae E. Choi ◽  
Roger E. Bumgarner ◽  
Adrian E. Raftery ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Microarray Data ◽  
Myeloid Leukemia ◽  
Bayesian Model Averaging ◽  
Expression Profiles ◽  
Blast Crisis ◽  
Probabilistic Method ◽  
Gene Expression Profiles ◽  
Chronic Phase ◽  
Microarray Dataset

Abstract Currently, limited molecular markers exist that can determine where in the spectrum of chronic myeloid leukemia (CML) progression an individual patient falls at diagnosis. Gene expression profiles can predict disease and prognosis, but most widely used microarray analytical methods yield lengthy gene candidate lists that are difficult to apply clinically. Consequently, we applied a probabilistic method called Bayesian model averaging (BMA) to a large CML microarray dataset. BMA, a supervised method, considers multiple genes simultaneously and identifies small gene sets. BMA identified 6 genes (NOB1, DDX47, IGSF2, LTB4R, SCARB1, and SLC25A3) that discriminated chronic phase (CP) from blast crisis (BC) CML. In CML, phase labels divide disease progression into discrete states. BMA, however, produces posterior probabilities between 0 and 1 and predicts patients in “intermediate” stages. In validation studies of 88 patients, the 6-gene signature discriminated early CP from late CP, accelerated phase, and BC. This distinction between early and late CP is not possible with current classifications, which are based on known duration of disease. BMA is a powerful tool for developing diagnostic tests from microarray data. Because therapeutic outcomes are so closely tied to disease phase, these probabilities can be used to determine a risk-based treatment strategy at diagnosis.

scholarly journals Identification of Key Genes and Pathways Associated with Mast Cells Resting in Meningioma

2020 ◽  
Author(s):  
Hui Xie ◽  
Xiao-hui Ding ◽  
Ce Yuan ◽  
Jin-jiang Li ◽  
Zhao-yang Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mast Cells ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Risk Model ◽  
Kegg Pathway ◽  
Expression Profiles ◽  
Receptor Interaction ◽  
Key Genes

Abstract Background: To identify candidate key genes and pathways related to mast cells resting in meningioma and the underlying molecular mechanisms of meningioma.Methods: Gene expression profiles of GSE43290 and GSE16581 datasets were obtained from the Gene Expression Omnibus (GEO) database. GO and KEGG pathway enrichments of DEGs were analyzed using the ClusterProfiler package in R. The protein-protein interaction network (PPI), and TF-miRNA- mRNA co-expression networks were constructed. Further, the difference in immune infiltration was investigated using the CIBERSORT algorithm.Results: A total of 1499 DEGs were identified between tumor and normal controls. The analysis of the immune cell infiltration landscape showed that the probability of distribution of memory B cells, regulatory T cells (Tregs), and resting mast cells in tumor samples were significantly higher than those in the controls. Moreover, through WGCNA analysis, the module related to mast cells resting contained 158 DEGs, and KEGG pathway analysis revealed that the DEGs were dominant in the TNF signaling pathway, cytokine-cytokine receptor interaction, and IL-17 signaling pathway. Survival analysis of hub genes related to mast cells resting showed that the risk model was constructed based on 9 key genes. The TF-miRNA- mRNA co-regulation network, including MYC-miR-145-5p, TNFAIP3-miR-29c-3p, and TNFAIP3-hsa-miR-335-3p, were obtained. Further, 36 nodes and 197 interactions in the PPI network were identified. Conclusions: The results of this study revealed candidate key genes, miRNAs, and pathways related to mast cells resting involved in meningioma development, providing potential therapeutic targets for meningioma treatment.

CD34+ obtained from High Sokal Risk Chronic Myeloid Leukemia (CML) Patients (PTS) Expresses Gene Profiles (GEP) Significantly Different From CD34+ Obtained From Low Sokal Risk Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2174-2174
Author(s):  
Carolina Terragna ◽  
Sandra Durante ◽  
Annalisa Astolfi ◽  
Francesca Palandri ◽  
Fausto Castagnetti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Chronic Phase ◽  
Chromosome 8 ◽  
Prognostic Scores ◽  
Training Set ◽  
Regulatory Pathways ◽  
Myc Gene

Abstract Abstract 2174 Poster Board II-151 Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disease which typically presents in chronic phase (CP), whose malignant progenitor cells proliferate rapidly, still retaining their ability to differentiate. If left untreated the disease can rapidly progress to accelerated phase and blast crisis. Although the treatment has been dramatically improved with introduction of Glivec therapy, the use of the Sokal and the Euro prognostic scores has remained an essential clinical tool to stratify CML patients at diagnosis based on different evolutive risk and to guide treatment decisions. To further optimize the management of the disease it is critical to gain a better understanding of regulatory pathways involved in the intrinsic heterogeneity of CML and propensity to progress. To that end our effort has been focused on identifying a molecular signature associated with a risk of the disease progression. Here we present data obtained from our study of gene expression profiles (GEP) aimed at identifying genes and pathways which could predict the disease course of CP-CML patients at the onset of the disease. The study was performed on highly enriched CD34+ cells from peripheral blood obtained from patients with untreated CML in CP. GEP was performed by using the Affymetrix HG-U133 Plus 2.0 platform. Raw data were normalized by using the RMA algorithm and filtered. Genes associated with Sokal risk score were selected by a moderate t-statistic (Limma package, p-value threshold = 0.01). Hierarchical clustering was performed with TIGR MeV. Overall, 34 pts were included in the present analysis. In the initial part of the study, the first 20 pts (the “training set”) were successfully assayed for global GEP and microarray data and were used to define a set of genes differentially expressed in high (H) (7 pts) vs. low (L) (13 pts) Sokal risk pts. We identified 84 probes sets and the clustering of their GEP showed an homogeneous pattern in H Sokal risk pts, where the most significantly involved process networks (as defined by GeneGo software) were: “Cell adhesion_Histamine H1 receptor signaling in the interruption of cell barrier integrity” (PLCB1, CALM1, PRKCA, PPPIR14A, MYL4), “Cytoskeleton remodeling_TGF and WNT” (ACTN1, CFL2, TCF7L2) and “Development_WNT signaling pathway” (WNT6, FZD3, TCF4, VEGF-A). Of interest, among the most significantly up-regulated genes, we identified PVT1, a non-coding gene located on chromosome 8, close to c-Myc gene, which encodes for several miRNA able to activate c-Myc gene transcription. Among the most significantly down-regulated genes is PLCB1, which we have recently described as being deleted in myelodysplastic syndromes and in acute myeloid leukemia. In the second part of the study, the 84 probes set were tested on an independent test set of 14 pts, including 4 H, and 10 L Sokal risk pts., thus showing that the GEP clustering displayed the same feature which we have observed in the training set. In conclusion, our study has identified a distinct array of genes at diagnosis which might be involved in driving the evolutive risk of CML and potentially, this approach could be of value to better define patients who may need an optimized treatment. Supported by:Novartis Oncology, TOPS Correlative Studies, PRIN, AIRC, AIL, FIRB 2006, Fondazione del Monte di Bologna e Ravenna. Disclosures: No relevant conflicts of interest to declare.

hOCT1 Gene Expression Might Predict Molecular Response In Patients with Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4838-4838
Author(s):  
Lurdes Zamora ◽  
Marta Cabezon ◽  
Concha Boqué ◽  
Silvia Marce ◽  
Jordi Ribera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Chronic Phase ◽  
Organic Cation Transporter ◽  
Initial Response ◽  
Molecular Response ◽  
Hematopoietic Malignancy

Abstract Abstract 4838 Introduction: Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy characterized by the presence of BCR/ABL fusion gene. The resulting protein has a high tyrosine kinase (TK) activity. The first-line treatment for CML is Imatinib, which allow the achievement of cytogenetic and molecular response in most of patients with CML in chronic phase. However, some patients do not respond to this treatment or lose their initial response. Imatinib has been reported to be incorporated into the cell through hOCT1 transporter (human organic cation transporter). The aim of this study was to determine whether the expression of hOCT1 at diagnosis of CML influenced the achievement of molecular response. Patients and Methods: We analyzed hOCT1 gene expression by quantitative PCR in 42 patients at diagnosis and 18 months after treatment with Imatinib. We compared the expression with the presence of compleat molecular response (CMR) at 18 months. We consider CMR when the Ratio (BCR-ABL/ABL)×100 was <0.1% (after International Scale correction). For statistical analysis methods we have used Kolmogorov-Smirnov and Mann-Whitney nonparametric methods. Results: Of the 42 patients, 2 were in hematological response, 22 were in cytogenetic response and 18 in CMR at 18 months. We found a higher hOCT1 gene expression at 18 month than at diagnosis (53.3 versus 29.6, p<0.001) in all patients (Figure 1). We have found some tendency of higher hOCT1 expression at diagnosis in patients with CMR at 18 months than in those who did not had (25.5 versus 18.8, p = 0.07) (Figure 2). Conclusions: Partially funded by FICJ-P-EF-09, RD06/0020/1056 de RTICC and Novartis. We want to thank Dr. David Marin for providing us plasmid for quantitative analysis. Disclosures: No relevant conflicts of interest to declare.

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