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PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features.
Teye, Emmanuel K; Sido, Abigail; Xin, Ping; Finnberg, Niklas K; Gokare, Prashanth; Kawasawa, Yuka I; Salzberg, Anna C; Shimko, Sara; Bayerl, Michael; Ehmann, W Christopher; Claxton, David F; Rybka, Witold B; Drabick, Joseph J; Wang, Hong-Gang; Abraham, Thomas; El-Deiry, Wafik S; Brodsky, Robert A; J Hohl, Raymond; Pu, Jeffrey J.
Afiliación
  • Teye EK; Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Sido A; Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Xin P; Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Finnberg NK; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
  • Gokare P; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
  • Kawasawa YI; Institute for Personalized Medicine and Departments of Pharmacology, Biochemistry and Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Salzberg AC; Institute for Personalized Medicine and Departments of Pharmacology, Biochemistry and Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Shimko S; Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Bayerl M; Department of Pathology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Ehmann WC; Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Claxton DF; Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Rybka WB; Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Drabick JJ; Department of Pathology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Wang HG; Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • Abraham T; Department of Pediatrics, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
  • El-Deiry WS; Department of Neural and Behavioral Science and the Microscopy Imaging Facility, Pennsylvania State University, Hershey, Pennsylvania, USA.
  • Brodsky RA; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
  • J Hohl R; Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Pu JJ; Penn State Hershey Cancer Institute and Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
Oncotarget ; 8(18): 29887-29905, 2017 May 02.
Article en En | MEDLINE | ID: mdl-28187452
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfotransferasas / Síndromes Mielodisplásicos / Leucemia Mieloide Aguda / Regulación Leucémica de la Expresión Génica / Inestabilidad Genómica Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Male Idioma: En Revista: Oncotarget Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfotransferasas / Síndromes Mielodisplásicos / Leucemia Mieloide Aguda / Regulación Leucémica de la Expresión Génica / Inestabilidad Genómica Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Male Idioma: En Revista: Oncotarget Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos