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      Transcriptomics-based validation of the relatedness of heterogeneous nuclear ribonucleoproteins to chronic lymphocytic leukemia as potential biomarkers of the disease aggressiveness

      , MSc, PhD

      Saudi Medical Journal

      Saudi Medical Journal

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          Abstract

          Objectives:

          To use independent transcriptomics data sets of cancer patients with prognostic information from public repositories to validate the relevance of our previously described chronic lymphocytic leukemia (CLL)-related proteins at the level of transcription (mRNA) to the prognosis of CLL.

          Methods:

          This is a validation study that was conducted at Majmaah University, Kingdom of Saudi Arabia between January-2017 and July-2018. Two independent data sets of CLL transcriptomics from Gene Expression Omnibus (GEO) with time-to-first treatment (TTFT) data (GSE39671; 130 patients) and information about overall survival (OS) (GSE22762; 107 patients) were used for the validation analyses. To further investigate the relatedness of a transcript of interest to other neoplasms, 6 independent data sets of cancer transcriptomics with prognostic information (1865 patients) from the cancer genomics atlas (TCGA) were used. Pathway-enrichment analyses were conducted using Reactome; and correlation analyses of gene expression were performed using Pearson score.

          Results:

          Nine of the CLL-related proteins exhibited transcript expression that predicted TTFT and 7 of the CLL-related proteins showed mRNA levels that predicted OS in CLL patients ( p≤0.05). Of these transcripts, 8 were different types of heterogeneous nuclear ribonucleoproteins ( HNRNPs); and 2 ( HNRNPUL2 and HIST1C1H) retained prognostic significance in the 2 independent data sets. Furthermore, genes that enriched CLL-related pathways ( p≤0.05; false discovery rate [FDR] ≤0.05) were found to correlate with the expression of HNRNPUL2 (Pearson score: ≥0.50; p<0.00001). Finally, increased expression of HNRNPUL2 was indicative of poor prognosis of various types of cancer other than CLL ( p<0.05).

          Conclusion:

          The cognate transcripts of 14 of our CLL-related proteins significantly predicted CLL prognosis.

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          Most cited references 29

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          Correlations between RNA and protein expression profiles in 23 human cell lines

          Background The Central Dogma of biology holds, in famously simplified terms, that DNA makes RNA makes proteins, but there is considerable uncertainty regarding the general, genome-wide correlation between levels of RNA and corresponding proteins. Therefore, to assess degrees of this correlation we compared the RNA profiles (determined using both cDNA- and oligo-based microarrays) and protein profiles (determined immunohistochemically in tissue microarrays) of 1066 gene products in 23 human cell lines. Results A high mean correlation coefficient (0.52) was obtained from the pairwise comparison of RNA levels determined by the two platforms. Significant correlations, with correlation coefficients exceeding 0.445, between protein and RNA levels were also obtained for a third of the specific gene products. However, the correlation coefficients between levels of RNA and protein products of specific genes varied widely, and the mean correlations between the protein and corresponding RNA levels determined using the cDNA- and oligo-based microarrays were 0.25 and 0.20, respectively. Conclusion Significant correlations were found in one third of the examined RNA species and corresponding proteins. These results suggest that RNA profiling might provide indirect support to antibodies' specificity, since whenever a evident correlation between the RNA and protein profiles exists, this can sustain that the antibodies used in the immunoassay recognized their cognate antigens.
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            B-cell receptor signaling in chronic lymphocytic leukemia.

            The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies. Recombinatorial and mutational patterns in the clonal immunoglobulin (Ig) of chronic lymphocytic leukemia (CLL) have revealed 2 major IgMD-expressing subsets and an isotype-switched variant, each developing from distinct B-cell populations. Tracking of conserved stereotypic features of Ig variable regions characteristic of U-CLL indicate circulating naive B cells as the likely cells of origin. In CLL, engagement of the BCR by antigen occurs in vivo, leading to down-regulated expression and to an unanticipated modulation of glycosylation of surface IgM, visible in blood cells, especially in U-CLL. Modulated glycoforms of sIgM are signal competent and could bind to environmental lectins. U-CLL cases express more sIgM and have increased signal competence, linking differential signaling responses to clinical behavior. Mapping of BCR signaling pathways identifies targets for blockade, aimed to deprive CLL cells of survival and proliferative signals. New inhibitors of BCR signaling appear to have clinical activity. In this Perspective, we discuss the functional significance of the BCR in CLL, and we describe strategies to target BCR signaling as an emerging therapeutic approach.
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              Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment.

              Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B-cells.
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                Author and article information

                Journal
                Saudi Med J
                Saudi Med J
                Saudi Medical Journal
                Saudi Medical Journal (Saudi Arabia )
                0379-5284
                2019
                : 40
                : 4
                : 328-338
                Affiliations
                From the Department of Medical Laboratories Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Kingdom of Saudi Arabia
                Author notes
                Address correspondence and reprint request to: Dr. Suliman A. Alsagaby, Department of Medical Laboratories Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Kingdom of Saudi Arabia. E-mail: s.alsaqaby@ 123456mu.edu.sa ORCID ID: orcid.org/0000-0002-2242-5638
                Article
                SaudiMedJ-40-328
                10.15537/smj.2019.4.23380
                6506648
                30957125
                Copyright: © Saudi Medical Journal

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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