title: PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features.
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.
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Emmanuel K
authors.initials: EK
authors.lastname: Teye
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Sido
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Xin
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Niklas K
authors.initials: NK
authors.lastname: Finnberg
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Gokare
authors.affiliation: Institute for Personalized Medicine and Departments of Pharmacology, Biochemistry and Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Yuka I
authors.initials: YI
authors.lastname: Kawasawa
authors.affiliation: Institute for Personalized Medicine and Departments of Pharmacology, Biochemistry and Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Salzberg
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Shimko
authors.affiliation: Department of Pathology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bayerl
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: W Christopher
authors.initials: WC
authors.lastname: Ehmann
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Claxton
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.|Department of Pathology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Witold B
authors.initials: WB
authors.lastname: Rybka
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Drabick
authors.affiliation: Department of Pediatrics, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: Department of Neural and Behavioral Science and the Microscopy Imaging Facility, Pennsylvania State University, Hershey, Pennsylvania, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Abraham
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
authors.affiliation: Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: J Hohl
authors.affiliation: Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.|Department of Pathology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Pu
mesh_terms: D001853:Bone Marrow / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D018450:Disease Progression; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D042822:Genomic Instability; D006801:Humans; D007438:Introns; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008954:Models, Biological; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; D009687:Nuclear Proteins; C561296:PIGN protein, human; D010770:Phosphotransferases
keywords: AML with myelodysplasia-related changes (AML-MRC); MDS; PIGN gene expression aberration; genomic instability; leukemogenesis