PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features
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Emmanuel K. Teye1,2, Abigail Sido1,2, Ping Xin1,2, Niklas K. Finnberg3, Prashanth Gokare3, Yuka I. Kawasawa4,5,6, Anna C. Salzberg4,5,6, Sara Shimko1,2, Michael Bayerl7, W. Christopher Ehmann1,2, David F. Claxton1,2, Witold B. Rybka1,2,7, Joseph J. Drabick1,2, Hong-Gang Wang8, Thomas Abraham9,10, Wafik S. El-Deiry3, Robert A. Brodsky11, Raymond J. Hohl1,2, Jeffrey J. Pu1,2,7
1Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania, USA
2Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA
3Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
4Institute for Personalized Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA
5Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania, USA
6Department of Biochemistry and Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania, USA
7Department of Pathology, Penn State University College of Medicine, Hershey, Pennsylvania, USA
8Department of Pediatrics, Penn State University College of Medicine, Hershey, Pennsylvania, USA
9Department of Neural and Behavioral Science, Pennsylvania State University, Hershey, Pennsylvania, USA
10Microscopy Imaging Facility, Pennsylvania State University, Hershey, Pennsylvania, USA
11Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Jeffrey J. Pu, email: [email protected]
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
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.
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