Pandolfi / Vogt Acute Promyelitic Leukemia

Molecular Genetics, Mouse Models and Targeted Therapy
1. Auflage 2007
ISBN: 978-3-540-34594-7
Verlag: Springer Berlin Heidelberg
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 313, 274 Seiten

Reihe: Current Topics in Microbiology and Immunology

Over the past 10 years, work on acute promyelocytic leukemia (APL) has become the paradigm of translational research that began with the discovery of a recurrent chromosomal translocation, followed by the identification of the genes and proteins involved, finding their molecular functions in transcriptional control, establishing mouse models and culminating in the development  of targeted therapy.

Autoren/Hrsg.

Pandolfi, Pier Paolo

Vogt, Peter K.

Inhaltsverzeichnis

1;List of Contents;5
2;List of Contributors;7
3;APL as a Paradigm in Biomedical Research: A Journey Toward the Cure;8
4;Mouse Models of Acute Promyelocytic Leukemia;10
4.1;1 Models;11
4.2;2 Cooperating Events;18
4.3;3 Pathogenesis, Conclusions;21
4.4;4 Immune Modulation of APL;22
4.5;5 Therapies;23
4.6;6 Arsenic Trioxide;25
4.7;7 Histone Deacetylase Inhibitors;29
4.8;8 Additional Investigational Therapies;30
4.9;9 Therapy, Conclusions;31
4.10;10 Perspectives;31
4.11;References;32
5;The PLZF Gene of t(11;17)-Associated APL;38
5.1;Summary;49
5.2;References;49
6;SUMO, the Three Rs and Cancer;56
6.1;1 Introduction;56
6.2;2 At the Chromosomal Level;58
6.3;3 DNA Replication and Repair;64
6.4;4 SUMO and Cancer: Caretakers and Gatekeepers;66
6.5;5 Conclusion;70
6.6;References;71
7;Emerging Role for MicroRNAs in Acute Promyelocytic Leukemia;80
7.1;1 Introduction;81
7.2;2 microRNAs;82
7.3;3 microRNAs and Hematopoietic Lineage Specificity;84
7.4;4 Regulation of miR-223 Expression Levels in Acute Promyelocytic Leukemia;85
7.5;5 C/EBPa and NFI- A;86
7.6;6 miR-223 Upstream Region;88
7.7;7 Concluding Remarks;89
7.8;References;90
8;The Theory of APL Revisited;92
8.1;1 Introduction;93
8.2;2 The Fusion Proteins of APL Are Oncogenes of the Early Myeloid Hematopoietic Compartment;94
8.3;3 X-RARa Proteins Are Necessary but Not Sufficient to Cause Leukemia and Represent Biologically Distinct RARa Mutants;95
8.4;4 RARa- X Proteins Do Play a Critical Role in APL Leukemogenesis, but Are Not Sufficient for Full- Blown Transformation;95
8.5;5 Multiple Genetic Hits in APL Pathogenesis;96
8.6;6 XMolecules Are Involved in the Control of the Cell Mitogenic and Survival Signals, and of Genomic Stability;97
8.7;7 The Crosstalk Between X and RAR/RXR Pathways;98
8.8;8 X Haploinsufficiency and Functional Interference of X-RARa and RARa- X with X- Regulated Pathways Is Critical for APL Leukemogenesis;99
8.9;9 The X Moiety Lends to the X-RARa Fusion Protein Distinct Gain- of- Function Proteins;100
8.10;10 Conclusions and Future Directions;100
8.11;References;103
9;Treatment of Acute Promyelocytic Leukemia by Retinoids;108
9.1;1 Background: Results of Chemotherapy Alone in APL;110
9.2;2 First Results Obtained with ATRA Alone in APL;112
9.3;3 ATRA Combined to Intensive Chemotherapy in Newly Diagnosed APL;113
9.4;4 Consolidation and Maintenance Treatment with ATRA in APL;114
9.5;5 Prognostic Factors in Patients Treated with ATRA and Chemotherapy;115
9.6;6 Unresolved Issues in the ATRA and Chemotherapy Combination Treatment of Newly Diagnosed APL;118
9.7;7 Role of Retinoids in the Treatment of Relapsing APL;120
9.8;8 APL Differentiation Syndrome (ATRA Syndrome) and Other Side Effects of ATRA;121
9.9;References;125
10;Arsenic Trioxide and Acute Promyelocytic Leukemia: Clinical and Biological;136
10.1;1 As2O3 as Single Treatment in Remission Induction;137
10.2;2 Dosage and Pharmacokinetics;137
10.3;3 As2O3 as Combined Treatment with ATRA in Remission Induction;140
10.4;4 Adverse Effects;141
10.5;5 Postremission Treatment and Survival Time;142
10.6;6 Molecular Mechanisms of Arsenic Action;143
10.7;7 Perspectives;146
10.8;References;147
11;Front Line Clinical Trials and Minimal Residual Disease Monitoring in Acute Promyelocytic Leukemia;152
11.1;1 Diagnostic Approach;153
11.2;2 Molecular Architecture of the t(15;17) and Definition of the RT- PCR Strategy;154
11.3;3 Technical Issues Related to RT-PCR Amplification;155
11.4;4 Strategies to Improve RT-PCR Monitoring and Quantitative Real- Time RT- PCR;156
11.5;5 Front-Line Therapy;157
11.6;References;160
12;Histone Deacetylase Inhibitors in APL and Beyond;164
12.1;1 Cancer Epigenetics and Histone Acetylation;165
12.2;2 The Histone Deacetylase Family;168
12.3;3 Histone Deacetylase Inhibitors;174
12.4;4 Future Directions;184
12.5;References;189
13;Monoclonal Antibody Therapy of APL;212
13.1;1 Introduction;212
13.2;2 Background;213
13.3;3 Therapies;216
13.4;4 Conclusion;221
13.5;References;222
14;Targeting APL Fusion Proteins by Peptide Interference;228
14.1;1 Introduction;229
14.2;2 Designing Therapeutic Peptides;231
14.3;3 Identifying Molecular Targets for Therapeutic Peptides;237
14.4;4 WhatWould the Clinical Applications of Peptide Interference Be in APL?;242
14.5;References;245
15;The Design of Selective and Non-selective Combination Therapy for Acute Promyelocytic Leukemia;252
15.1;1 ATRA Induces APL Cell Differentiation by Overcoming PML- RARa Transcriptional Repression;254
15.2;2 As2O3 Induces Differentiation of APL Cells Through a PML- RARa Degradation- Dependent Pathway;256
15.3;3 As2O3 Induces Apoptosis of APL Cells Through a PML- RARa Degradation- Independent Pathway;257
15.4;4 Anthracycline Induces Cell Death of APL Cells;258
15.5;5 Effects of a Combination of As2O3 and ATRA on APL Cells;259
15.6;6 The Effects of ATRA Combined with Daunorubicin on APL Cells;261
15.7;7 Effects of As2O3 and Anthracyclines in Combination on APL Cells;262
15.8;8 Histone Deacetylase Inhibitors Enhance ATRA-Induced Differentiation in APL Cells;262
15.9;9 Novel Agents That Enhance ATRA-Induced Differentiation in APL Cells;264
15.10;10 Design of Combination Selective and Non-selective Therapy of APL;265
15.11;References;267
16;Subject Index;278