PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features
| Autor: | Yuka Imamura Kawasawa, David F. Claxton, Michael G. Bayerl, Joseph J. Drabick, Niklas Finnberg, Sara Shimko, Raymond J. Hohl, Thomas Abraham, Jeffrey J. Pu, Witold B. Rybka, Anna C. Salzberg, Robert A. Brodsky, W. Christopher Ehmann, Abigail Sido, Hong Gang Wang, Prashanth Gokare, Emmanuel K. Teye, Wafik S. El-Deiry, Ping Xin |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Genome instability Oncology Gerontology Male medicine.medical_specialty Gene Expression Array Cell Cycle Proteins Spindle Apparatus Models Biological leukemogenesis Protein expression Genomic Instability 03 medical and health sciences Bone Marrow Internal medicine Gene expression MDS AML with myelodysplasia-related changes (AML-MRC) Medicine Humans Transcriptional activity Hematology business.industry Gene Expression Regulation Leukemic Gene Expression Profiling Phosphotransferases Myeloid leukemia Computational Biology Nuclear Proteins Exons Sequence Analysis DNA Genes p53 Introns Gene expression profiling Leukemia Myeloid Acute 030104 developmental biology Cell Transformation Neoplastic Gene Knockdown Techniques Myelodysplastic Syndromes Mutation Disease Progression Female business PIGN gene expression aberration Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Emmanuel K. Teye 1, 2 , Abigail Sido 1, 2 , Ping Xin 1, 2 , Niklas K. Finnberg 3 , Prashanth Gokare 3 , Yuka I. Kawasawa 4, 5, 6 , Anna C. Salzberg 4, 5, 6 , Sara Shimko 1, 2 , Michael Bayerl 7 , W. Christopher Ehmann 1, 2 , David F. Claxton 1, 2 , Witold B. Rybka 1, 2, 7 , Joseph J. Drabick 1, 2 , Hong-Gang Wang 8 , Thomas Abraham 9, 10 , Wafik S. El-Deiry 3 , Robert A. Brodsky 11 , Raymond J.Hohl 1, 2 , Jeffrey J. Pu 1, 2, 7 1 Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania, USA 2 Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA 3 Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA 4 Institute for Personalized Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA 5 Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania, USA 6 Department of Biochemistry and Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania, USA 7 Department of Pathology, Penn State University College of Medicine, Hershey, Pennsylvania, USA 8 Department of Pediatrics, Penn State University College of Medicine, Hershey, Pennsylvania, USA 9 Department of Neural and Behavioral Science, Pennsylvania State University, Hershey, Pennsylvania, USA 10 Microscopy Imaging Facility, Pennsylvania State University, Hershey, Pennsylvania, USA 11 Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence to: Jeffrey J. Pu, email: jeffreypu@gmail.com Keywords: PIGN gene expression aberration, MDS, AML with myelodysplasia-related changes (AML-MRC), genomic instability, leukemogenesis Received: November 25, 2016 Accepted: January 11, 2017 Published: February 07, 2017 ABSTRACT Previous studies have linked increased frequency of glycosylphosphatidylinositol-anchor protein (GPI-AP) deficiency with genomic instability and the risk of carcinogenesis. However, the underlying mechanism is still not clear. A randomForest analysis of the gene expression array data from 55 MDS patients (GSE4619) demonstrated a significant (p = 0.0007) correlation (Pearson r =-0.4068) between GPI-anchor biosynthesis gene expression and genomic instability, in which PIGN, a gene participating in GPI-AP biosynthesis, was ranked as the third most important in predicting risk of MDS progression. Furthermore, we observed that PIGN gene expression aberrations (increased transcriptional activity but diminished to no protein production) were associated with increased frequency of GPI-AP deficiency in leukemic cells during leukemic transformation/progression. PIGN gene expression aberrations were attributed to partial intron retentions between exons 14 and 15 resulting in frameshifts and premature termination which were confirmed by examining the RNA-seq data from a group of AML patients (phs001027.v1.p1). PIGN gene expression aberration correlated with the elevation of genomic instability marker expression that was independent of the TP53 regulatory pathway. Suppression/elimination of PIGN protein expression caused a similar pattern of genomic instability that was rescued by PIGN restoration. Finally, we found that PIGN bound to the spindle assembly checkpoint protein, MAD1, and regulated its expression during the cell cycle. In conclusion, PIGN gene is crucial in regulating mitotic integrity to maintain chromosomal stability and prevents leukemic transformation/progression. |
| Databáze: | OpenAIRE |
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