PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features

Emmanuel K. Teye, Abigail Sido, Ping Xin, Niklas K. Finnberg, Prashanth Gokare, Yuka Imamura, Anna C. Salzberg, Sara Shimko, Michael Bayerl, W. Christopher Ehmann, David Claxton, Witold Rybka, Joseph Drabick, Hong-Gang Wang, Thomas Abraham, Wafik S. El-Deiry, Robert A. Brodsky, Raymond J.Hohl, Jeffrey Pu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Previous studies have linked increased frequency of glycosylphosphatidylinositolanchor 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 RNAseq 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.

Original languageEnglish (US)
Pages (from-to)29887-29905
Number of pages19
JournalOncotarget
Volume8
Issue number18
DOIs
StatePublished - Jan 1 2017

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Genomic Instability
Acute Myeloid Leukemia
Gene Expression
Protein Deficiency
M Phase Cell Cycle Checkpoints
Chromosomal Instability
Proteins
Protein Biosynthesis
Introns
Genes
Exons
Cell Cycle
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Teye, Emmanuel K. ; Sido, Abigail ; Xin, Ping ; Finnberg, Niklas K. ; Gokare, Prashanth ; Imamura, Yuka ; Salzberg, Anna C. ; Shimko, Sara ; Bayerl, Michael ; Ehmann, W. Christopher ; Claxton, David ; Rybka, Witold ; Drabick, Joseph ; Wang, Hong-Gang ; Abraham, Thomas ; El-Deiry, Wafik S. ; Brodsky, Robert A. ; J.Hohl, Raymond ; Pu, Jeffrey. / PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features. In: Oncotarget. 2017 ; Vol. 8, No. 18. pp. 29887-29905.
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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 glycosylphosphatidylinositolanchor 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 RNAseq 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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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; Imamura, Yuka; Salzberg, Anna C.; Shimko, Sara; Bayerl, Michael; Ehmann, W. Christopher; Claxton, David; Rybka, Witold; Drabick, Joseph; Wang, Hong-Gang; Abraham, Thomas; El-Deiry, Wafik S.; Brodsky, Robert A.; J.Hohl, Raymond; Pu, Jeffrey.

In: Oncotarget, Vol. 8, No. 18, 01.01.2017, p. 29887-29905.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features

AU - Teye, Emmanuel K.

AU - Sido, Abigail

AU - Xin, Ping

AU - Finnberg, Niklas K.

AU - Gokare, Prashanth

AU - Imamura, Yuka

AU - Salzberg, Anna C.

AU - Shimko, Sara

AU - Bayerl, Michael

AU - Ehmann, W. Christopher

AU - Claxton, David

AU - Rybka, Witold

AU - Drabick, Joseph

AU - Wang, Hong-Gang

AU - Abraham, Thomas

AU - El-Deiry, Wafik S.

AU - Brodsky, Robert A.

AU - J.Hohl, Raymond

AU - Pu, Jeffrey

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Previous studies have linked increased frequency of glycosylphosphatidylinositolanchor 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 RNAseq 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.

AB - Previous studies have linked increased frequency of glycosylphosphatidylinositolanchor 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 RNAseq 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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