Pan-Cancer Study of INPP4B Reveals its Unexpected Oncogene-Like Role and Prognostic Significance
Year: 2017
Type: dissertation
Abstract: The work presented in this thesis demonstrates and explores the unexpected oncogenic role of a previously known tumor suppressor inositol polyphosphate-4-phosphatase, type-II (INPP4B). Specifically, INPP4B-high AML was found to be associated with poor response to therapy, and shorter overall- and event-free survival. Multivariate analysis revealed that INPP4B expression status improves oneâ s ability to predict patient outcome when added to current prognostic models. Furthermore, INPP4B-high identifies a poor risk patient subgroup in the cytogenetically normal patient subpopulation. In vitro overexpression of INPP4B in AML cell lines revealed that INPP4B contributes to a more aggressive AML disease by enhancing colony forming potential, increasing proliferation, and increasing drug resistance. In addition to being the first in identifying INPP4Bâ s prognostic significance in AML, this thesis is amongst the first studies to uncover the unexpected oncogenic function of this previously known tumor suppressor. Next, to identify transcriptional regulators of INPP4B in AML, and characterize the pan-cancer prognostic significance of INPP4B expression status, I developed subgroup identifier (SubID), a non-median dichotomization tool for heterogeneous populations. Using SubID, I identified significant co-expression between INPP4B and the transcription factor EVI1. In vitro validation revealed EVI1 knockdown in EVI1-high AML cell lines is associated with a significant decrease INPP4B levels. Furthermore, chromatin immunoprecipiation demonstrated EVI1 binding to the INPP4B transcription start site region. Next, in my pan-cancer analysis with SubID, I identified that INPP4B expression may be associated with patient survival in 13 different cancer types. Following stringent multiple testing and permutation corrections, I observed that INPP4B-low expression status was associated with shorter survival in kidney clear cell, liver hepatocellular, and bladder urothelial carcinomas. Conversely, INPP4B-low status was associated with longer survival in pancreatic adenocarcinoma. The unexpected oncogene-like prognostic significance of INPP4B in pancreatic adenocarcinoma was cross-validated in two additional independent pancreatic cancer datasets. Overall, the work presented in this thesis provides evidence that INPP4B expression status is associated with patient outcome in both a tumor-suppressive and oncogenic manner depending on the context. In vitro work demonstrates that overexpression of INPP4B in AML contributes to traits associated with a more aggressive disease in a causative rather than associative manner.
Source: TSpace (University of Toronto)
Author: Irakli Dzneladze
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2896561922