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PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features
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 pat...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444711/ https://www.ncbi.nlm.nih.gov/pubmed/28187452 http://dx.doi.org/10.18632/oncotarget.15136 |
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author | 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. Hohl, Raymond J. Pu, Jeffrey J. |
author_facet | 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. Hohl, Raymond J. Pu, Jeffrey J. |
author_sort | Teye, Emmanuel K. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5444711 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-54447112017-06-01 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. Hohl, Raymond J. Pu, Jeffrey J. Oncotarget Research Paper 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. Impact Journals LLC 2017-02-07 /pmc/articles/PMC5444711/ /pubmed/28187452 http://dx.doi.org/10.18632/oncotarget.15136 Text en Copyright: © 2017 Teye et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper 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. Hohl, Raymond J. Pu, Jeffrey J. PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features |
title | PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features |
title_full | PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features |
title_fullStr | PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features |
title_full_unstemmed | PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features |
title_short | PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features |
title_sort | pign gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444711/ https://www.ncbi.nlm.nih.gov/pubmed/28187452 http://dx.doi.org/10.18632/oncotarget.15136 |
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