Mechanisms of Mutated PPM1D in Pediatric Brain Tumorigenesis Open Access

Abstract

Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric brainstem tumor with a poor prognosis. It is not amenable to surgical resection and does not respond to chemotherapy. Radiation, the standard therapy, prolongs survival by a few months leading to a median survival of only 9 months. Sequencing studies of DIPG have revealed that this tumor is biologically distinct from adult gliomas, and that it frequently harbors mutations in genes including H3F3A, HIST1H3B, TP53, PDGFRA, and PPM1D. PPM1D is PP2C serine/threonine phosphatase that targets DNA damage response proteins including p53, ATM, ATR, CHK1, and γH2A.X. It also regulates maturation of immune cells, maintenance of stem cells, and when overexpressed, promotes tumorigenesis of malignancies such as breast cancer and medulloblastoma. When mutated in DIPG, PPM1D promotes DIPG viability in vitro and in vivo. Inhibition of mutated PPM1D reduces cell proliferation, increases in vivo survival, increases apoptosis, and sensitizes DIPG to the effects of ionizing radiation. Inhibition of mutated PPM1D is therefore, a potentially viable strategy for DIPG treatment. Inhibitors of other targets have also shown preclinical efficacy in suppressing DIPG.  These include PDGFR inhibitors and epigenetic modulators. PPM1D and other identified targets for DIPG therapy should be evaluated for clinical efficacy to improve the prognosis of this almost uniformly fatal pediatric tumor.

Table of Contents

Chapter 1 1

1 Introduction 1

1.1 DIPG epidemiology, clinical features, and treatment 1

1.2 DIPG molecular features: Histone mutations 5

1.3 Other mutations in DIPG 7

1.4 PPM1D biochemistry and expression 8

1.5 PPM1D phosphatase regulates the DNA damage pathway and cell cycle 9

1.6 Physiological roles of PPM1D 13

1.7 PPM1D is necessary for male fertility in mice 14

1.8 PPM1D is required for immune cell development and hematopoietic stem cell regeneration 14

1.9 PPM1D is expressed in intestinal stem cells and inhibits apoptosis in colon pre-cancerous cells 18

1.10 PPM1D promotes mammary development and breast cancer 19

1.11 PPM1D promotes brain development and brain tumors 21

1.12 PPM1D inhibition in the treatment of cancer 23

1.13 Scope of this dissertation 24

Chapter 2 26

2. Inhibition of mutant PPM1D enhances DNA damage response and growth suppressive effects of ionizing radiation in diffuse intrinsic pontine glioma 26

2.1 Abstract 27

2.2 Importance of the Study 29

2.3 Introduction 30

2.4 Materials and Methods 32

2.5 Results 40

2.6 Discussion 56

2.7 Supplemental Figures 61

Chapter 3 77

3 Discussion 77

3.1 DIPG background 77

3.2 DIPG molecular alterations 77

3.3 Modeling brain tumors 78

3.4 DIPG drug target identification and verification 82

3.5 Conclusions 98

REFERENCES 99

About this Dissertation

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Cancer Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Cell Biology, Molecular
Keyword	PPM1D DIPG
Committee Chair / Thesis Advisor	Robert Craig Castellino, Emory University
Committee Members	Curtis Henry, Emory University David Yu, Emory University Wei Zhou, Emory University Dolores Hambardzumyan, Mount Sinai

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