Bcl-2 Family Protein Regulation in Differentiating and Malignant Plasma Cells Pubblico

Abstract

The maturation, selection and extended survival of plasma cells requires the dynamic interactions of the Bcl-2 family of proteins that control the induction of apoptosis. Cellular processes such as proliferation, differentiation and stress response increase the pro-apoptotic signaling in a cell. Cells must counter pro-apoptotic signals with anti-apoptotic signaling in order to survive. Thus the cell establishes apoptotic checkpoints to guard against diseased and malignant cells. One such checkpoint occurs during plasma cell differentiation when the cell must activate the unfolded protein response (UPR) in order to increase the capacity of the endoplasmic reticulum (ER). In both a murine lymphoma cell line and a primary murine B cell model of plasma cell differentiation we observed activation of the UPR including ATF4 and CHOP activation. This signaling included induction of Bim and inhibition of Bcl-2 and Mcl-1. Differentiation also induced Bcl-xL, which was necessary to protect from CHOP-induced apoptosis. These studies demonstrate a previously undescribed Bcl-xL-dependent state in plasma cell differentiation. Waldenström macroglobulinemia (WM) is a malignancy of lymphoplasmacytoid cells that secrete monoclonal pentameric IgM. Because the disease has a high prevalence of activating mutations that signal through NF-κB and consists of cells at the intersection between B cell and plasma cell we hypothesized that WM cells would display a Bcl-xL-dependency similar to differentiating plasma cells. In our examination of WM patient expression data we observed that plasma cell phenotype WM cells express both pro- and anti-apoptotic Bcl-2 family members at levels similar to normal plasma cells and lower than with multiple myeloma malignant plasma cells. WM cell lines displayed similarly low expression of pro-apoptotic Bcl-2 proteins. In two cell lines, low expression of Bim was due to overexpression of miR-155, which is common in WM and inhibits FoxO3a, an important transcription factor in the induction of Bim. These studies demonstrate how the apoptotic threshold of a malignant cell is set by both its normal physiology and its cancer physiology and that agents that induce mitochondrial priming by targeting both physiological and cancer-specific pathways, are necessary to efficiently lower the apoptotic threshold and kill the cancer cell.

Table of Contents

I. INTRODUCTION 1

A. Plasma Cell Differentiation 2

B. The Unfolded Protein Response 6

1. Mechanics of the UPR 6

2. The physiological UPR of plasma cell differentiation 7

C. Apoptosis and the BCL-2 Family 10

1. Intrinsic pathway of apoptosis 10

2. Extrinsic pathway of apoptosis 11

D. B Cell Development and the Bcl-2 Family 15

E. Mitochondrial Priming and Apoptotic Threshold 17

F. Plasma Cell Malignancy 19

1. Multiple myeloma 19

2. Waldenström macroglobulinemia 20

G. Statement of Problem 22

II. BCL-2 FAMILY DYNAMICS DURING NORMAL MURINE PLASMA CELL DIFFERENTIATION 25

A. Abstract 26

B. Introduction 27

C. Experimental Procedures 30

D. Results 34

E. Discussion 41

F. Acknowledgements 44

III. BCL-2 FAMILY REGUATION OF APOPTOSIS IN WALDENSTRÖM MACROGLOBULINEMIA 52

A. Abstract 53

B. Introduction 54

C. Methods 57

D. Results 60

E. Discussion 67

F. Acknowledgements 71

G. Supplemental Methods 79

IV. DISCUSSION 86

A. Implications of Plasma Cell Differentiation Studies 86

1. Caveats and opportunities for further study 89

2. Implications for future research 90

B. Implications from Waldenström Macroglobulinemia Studies 93

1. Caveats and opportunities for further study 94

2. Implications for future research 96

C. Apoptotic Checkpoints in Normal and Malignant Plasma Cells 99

1. The ER stress-induced apoptotic checkpoint in plasma cell differentiation 99

2. Low expression of pro-apoptotic protein in WM redefines the apoptotic checkpoint. 101

3. What is normal and what is cancer 101

V. REFFERENCES 106

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology
Parola chiave	UPR Apoptosis Immunology Plasma Cell Waldenstrom Macroglobulinemia Bcl-2 Family
Committee Chair / Thesis Advisor	Boise, Lawrence, Emory University
Committee Members	Galipeau, Jacques, Emory University Chen, Jing, Emory University Iwakoshi, Neal N., Emory University Speck, Sam, Emory University

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