THE NOVEL MECHANISTIC ROLE OF PIGN IN LEUKEMIA PROGRESSION
Open Access
- Author:
- Teye, Emmanuel Kwame
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- July 25, 2017
- Committee Members:
- Jeffrey J Pu, Dissertation Advisor/Co-Advisor
Jong Kak Yun, Committee Chair/Co-Chair
Hong-Gang Wang, Committee Member
Douglas B Stairs, Committee Member
Gregory Steven Yochum, Outside Member - Keywords:
- myelodysplastic syndrome
acute myeloid leukemia
PIGN
chromosomal instability
risk-stratification
biomarker
spindle assembly checkpoint
leukemia
mitotic exit
GPI anchor biosynthesis
cancer
cell cycle
mitosis - Abstract:
- Genomic instability plays a pivotal role in the leukemia progression of myelodysplastic syndromes (MDS). However, the precise genetic cause and the underlying mechanisms of MDS leukemia progression or transformation to acute myeloid leukemia (AML) remain elusive. Moreover, the current approach to MDS progression risk-stratification using the International Prognostic Scoring System (IPSS) or WHO Prognostic Scoring System (WPSS) is limited and fails to address the dynamic nature of the disease. This presents a need for the identification of novel prognostic markers and a better understanding of the mechanisms involved. In this study, phosphatidylinositol glycan anchor biosynthesis, class N (PIGN), a gene encoding an enzyme participating in the final steps of the glycophosphatidylinositol-anchored protein (GPI-AP) biosynthesis pathway and a cancer chromosomal instability (CIN) suppressor, was highly ranked as a predictor of the risk of MDS leukemia progression. We also observed the progressive loss of PIGN during MDS progression to AML. Moreover, PIGN gene expression aberrations (i.e. increased gene expression but diminished to no protein production) were observed in a subset of high-risk MDS and AML patients with myelodysplasia-related changes. PIGN gene expression aberrations were associated with increased frequency of GPI-AP deficiency in leukemic cells and correlated with the elevation of genomic instability that was independent of the TP53 regulatory pathway. PIGN gene expression aberrations were attributed to novel partial intron retentions between exons 14 and 15 resulting in frameshifts and premature termination. Interestingly, in an MDS leukemia progression model, this mutation was identified in the leukemia stage (i.e. MDS-L) cells but was absent in the MDS stage (i.e. MDS92) cells. Transient suppression or ablation of PIGN induced DNA damage response which was rescued following PIGN restoration. We also observed an increase in the frequency of CIN with PIGN loss. Moreover, PIGN physically interacted with and/or regulated the spindle assembly checkpoint via MAD1, MAD2, MPS1, and BUBR1. Thus, PIGN is crucial in the regulation of mitotic integrity for the maintenance of chromosomal stability and ultimately prevents leukemic transformation/progression. This study for the first time identified PIGN as a prognostic marker of MDS transformation and revealed the link between PIGN gene expression aberration, genomic instability, and MDS progression/leukemia transformation. PIGN gene expression aberration is associated with genomic instability and leukemogenesis and could serve as a basis for improved risk-stratification of MDS patients.