Acute Promyelitic Leukemia (eBook)

List of Contents 5
List of Contributors 7
APL as a Paradigm in Biomedical Research: A Journey Toward the Cure 8
Mouse Models of Acute Promyelocytic Leukemia 10
1 Models 11
2 Cooperating Events 18
3 Pathogenesis, Conclusions 21
4 Immune Modulation of APL 22
5 Therapies 23
6 Arsenic Trioxide 25
7 Histone Deacetylase Inhibitors 29
8 Additional Investigational Therapies 30
9 Therapy, Conclusions 31
10 Perspectives 31
References 32
The PLZF Gene of t(11 17)-Associated APL
Summary 49
References 49
SUMO, the Three Rs and Cancer 56
1 Introduction 56
2 At the Chromosomal Level 58
3 DNA Replication and Repair 64
4 SUMO and Cancer: Caretakers and Gatekeepers 66
5 Conclusion 70
References 71
Emerging Role for MicroRNAs in Acute Promyelocytic Leukemia 80
1 Introduction 81
2 microRNAs 82
3 microRNAs and Hematopoietic Lineage Specificity 84
4 Regulation of miR-223 Expression Levels in Acute Promyelocytic Leukemia 85
5 C/EBPa and NFI- A 86
6 miR-223 Upstream Region 88
7 Concluding Remarks 89
References 90
The Theory of APL Revisited 92
1 Introduction 93
2 The Fusion Proteins of APL Are Oncogenes of the Early Myeloid Hematopoietic Compartment 94
3 X-RARa Proteins Are Necessary but Not Sufficient to Cause Leukemia and Represent Biologically Distinct RARa Mutants 95
4 RARa- X Proteins Do Play a Critical Role in APL Leukemogenesis, but Are Not Sufficient for Full- Blown Transformation 95
5 Multiple Genetic Hits in APL Pathogenesis 96
6 XMolecules Are Involved in the Control of the Cell Mitogenic and Survival Signals, and of Genomic Stability 97
7 The Crosstalk Between X and RAR/RXR Pathways 98
8 X Haploinsufficiency and Functional Interference of X-RARa and RARa- X with X- Regulated Pathways Is Critical for APL Leukemogenesis 99
9 The X Moiety Lends to the X-RARa Fusion Protein Distinct Gain- of- Function Proteins 100
10 Conclusions and Future Directions 100
References 103
Treatment of Acute Promyelocytic Leukemia by Retinoids 108
1 Background: Results of Chemotherapy Alone in APL 110
2 First Results Obtained with ATRA Alone in APL 112
3 ATRA Combined to Intensive Chemotherapy in Newly Diagnosed APL 113
4 Consolidation and Maintenance Treatment with ATRA in APL 114
5 Prognostic Factors in Patients Treated with ATRA and Chemotherapy 115
6 Unresolved Issues in the ATRA and Chemotherapy Combination Treatment of Newly Diagnosed APL 118
7 Role of Retinoids in the Treatment of Relapsing APL 120
8 APL Differentiation Syndrome (ATRA Syndrome) and Other Side Effects of ATRA 121
References 125
Arsenic Trioxide and Acute Promyelocytic Leukemia: Clinical and Biological 136
1 As2O3 as Single Treatment in Remission Induction 137
2 Dosage and Pharmacokinetics 137
3 As2O3 as Combined Treatment with ATRA in Remission Induction 140
4 Adverse Effects 141
5 Postremission Treatment and Survival Time 142
6 Molecular Mechanisms of Arsenic Action 143
7 Perspectives 146
References 147
Front Line Clinical Trials and Minimal Residual Disease Monitoring in Acute Promyelocytic Leukemia 152
1 Diagnostic Approach 153
2 Molecular Architecture of the t(15 17) and Definition of the RT- PCR Strategy
3 Technical Issues Related to RT-PCR Amplification 155
4 Strategies to Improve RT-PCR Monitoring and Quantitative Real- Time RT- PCR 156
5 Front-Line Therapy 157
References 160
Histone Deacetylase Inhibitors in APL and Beyond 164
1 Cancer Epigenetics and Histone Acetylation 165
2 The Histone Deacetylase Family 168
3 Histone Deacetylase Inhibitors 174
4 Future Directions 184
References 189
Monoclonal Antibody Therapy of APL 212
1 Introduction 212
2 Background 213
3 Therapies 216
4 Conclusion 221
References 222
Targeting APL Fusion Proteins by Peptide Interference 228
1 Introduction 229
2 Designing Therapeutic Peptides 231
3 Identifying Molecular Targets for Therapeutic Peptides 237
4 WhatWould the Clinical Applications of Peptide Interference Be in APL? 242
References 245
The Design of Selective and Non-selective Combination Therapy for Acute Promyelocytic Leukemia 252
1 ATRA Induces APL Cell Differentiation by Overcoming PML- RARa Transcriptional Repression 254
2 As2O3 Induces Differentiation of APL Cells Through a PML- RARa Degradation- Dependent Pathway 256
3 As2O3 Induces Apoptosis of APL Cells Through a PML- RARa Degradation- Independent Pathway 257
4 Anthracycline Induces Cell Death of APL Cells 258
5 Effects of a Combination of As2O3 and ATRA on APL Cells 259
6 The Effects of ATRA Combined with Daunorubicin on APL Cells 261
7 Effects of As2O3 and Anthracyclines in Combination on APL Cells 262
8 Histone Deacetylase Inhibitors Enhance ATRA-Induced Differentiation in APL Cells 262
9 Novel Agents That Enhance ATRA-Induced Differentiation in APL Cells 264
10 Design of Combination Selective and Non-selective Therapy of APL 265
References 267
Subject Index 278