Acute Myelogenous Leukemia (eBook)

Lalitha Nagarajan is an Associate Professor, Department of Molecular Genetics, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas. 

Contents 5
Contributors 7
The Leukemia Stem Cell 10
Introduction and Historical Perspective 10
The Hematopoietic Stem Cell 11
Concept and Definition 11
Isolation of HSCs 12
HSC Characterization 12
The Hematopoietic Stem Cell Niche 13
The Leukemia Stem Cell 14
Cancer Stem Cell: Concept and Definition 14
Models of Leukemogenesis 15
LSC Phenotype and Function 15
Molecular Pathways Regulating HSCs and LSCs 17
Cellular HSC and LSC Regulators 19
Clinical Significance 19
LSCs, Drug Resistance, and Relapse 19
LSCs and Strategies to Cure Leukemia 20
References 21
Epigenetic Mechanisms in AML - A Target for Therapy 27
Introduction 27
DNA Methylation and DNA Methyltransferase (DNMT) 28
DNA Methylation in AML 29
Histone Modifications 32
Histone Alterations in AML 33
Epigenetic Therapy 35
DNMT Inhibitors 36
5-Azacytidine (Azacitidine) 37
5-Aza-2’-deoxycytidine (Decitabine) 37
Mechanisms of Response to Hypomethylating Agents 38
HDAC Inhibitors 39
Combination Epigenetic Therapy 39
Conclusions 40
References 40
Chromosomal Translocations in AML: Detection and Prognostic Significance 49
Introduction 49
Acute Myeloid Leukemia (AML) 50
Classification of AML 50
Cytogenetic Analysis in AML 53
Recurrent Chromosomal Aberrations in AML 55
Chromosome 1 56
t(1 3)(p36
t(1 7)(q10
t(1 11)(p32
t(1 22)(p13
Chromosome 3 56
inv(3)(q21q26), ins(3 3)(q26
t(3 5)(q21-25
t(3 8)(q26
t(3 21)(q26
Chromosome 6p 57
t(6 9)(p23
t(6 11)(q27
Chromosome 7 58
t(7 11)(p15
t(7 21)(p22
Chromosome 8 58
t(8 9)(p21-23
t(8 16)(p11
t(8 21)(q22
Chromosome 9 59
t(9 22)(q34
Chromosomes 10 and 11 59
t(11 17)(q23
t(11 19)(q23
t(11 20)(p15
Chromosome 15 60
t(15 17)(q22
Chromosome 16 61
inv/del(16)(p13q22)/del(16)(q22)/t(16 16)(p13
Chromosome 17 61
i(17)(q10) 61
Clinical Relevance of Chromosome Abnormalities in AML 61
Conclusions/Future Directions 62
References 63
Chromosomal Deletions in AML 67
Introduction 67
Chromosome 4q 69
Chromosome 5q 69
Chromosome 7q 71
Chromosome 11q 71
Chromosome 17p 71
Chromosome 20q 72
Mechanisms of Deletions 72
Conclusions 73
References 73
Genes Predictive of Outcome and Novel Molecular Classification Schemes in Adult Acute Myeloid Leukemia 75
AML Diagnostics 76
Cytogenetic Analyses and AML Prognostics 77
Molecular Genetics and AML Prognostics 78
Gene Expression Profiling and AML Prognostics 81
Prediction of Known Classes by Gene Expression Profiling 82
Identification of Novel Subtypes of AML by Gene Expression Profiling 83
Outcome Prediction Using Genes Expression Profiling 85
Conclusions and Perspectives Regarding Prognostics of AML 86
References 87
Receptor Tyrosine Kinase Alterations in AML - Biology and Therapy 92
Introduction 92
Receptor Tyrosine Kinase Activation and Downstream Effectors 93
FLT3 Mutations 97
KIT Mutations 99
Other RTKs, c-FMS, and PDGFR 100
Small Molecule Inhibitors as Therapeutic Options 101
FLT3 Inhibitors 102
KIT and Other Small Molecule Inhibitors 104
Future Directions 105
References 106
Lineage-Specific Transcription Factor Aberrations in AML 116
Leukemic Stem Cells as a Model for Cancer Development 116
The Role of Transcription Factors for Normal Hematopoietic Stem Cell Function 117
Differing Expression Levels of Lineage-Restricted Transcription Factors Regulate Differentiation Fates 119
Transcription Factors Play a Crucial Role in Human AML 119
Transcription Factor Activity of the Myeloid Key Transcription Factor CEBPA Is Critically Suppressed in AML Patients 120
CEBPA Mutations in AML Patients 120
Suppression of CEBPA Expression in AML Patients 121
Posttranscriptional Suppression of CEBPA in AML Patients 122
Posttranslational Inhibition of CEBPA in AML Patients 122
Alterations of the AML1/RUNX1 Transcription Factor in AML 123
Heterozygous RUNX1 Mutations and the Concept of Haploinsufficiency 123
Biallelic RUNX1 Mutations in the AML M0 Subtype 124
RUNX1 Mutations Evolving as Secondary Leukemia from Myelodysplastic Syndrome (MDS) or Therapy-Related MDS 124
Acquired Trisomy 21 and Non-MO Myeloid Malignancy 124
RUNX1 Mutations in Familial Leukemia (FPD-AML) 124
Hypomorphic PU.1 Function in AML 125
PU.1 Mutations in AML 125
PU.1 Is Suppressed in Acute Promyelocytic Leukemia (APL) 125
Hypomorphic PU.1 Function Acts Leukemogenic 126
Deregulated GATA1 Function in AML 126
Concluding Remarks 128
References 128
Proleukemic RUNX1 and CBFbeta Mutations in the Pathogenesis of Acute Leukemia 133
Introduction 134
The RUNX1/CBFbeta Transcription Factor 134
RUNX1 and CBFbeta in Hematopoiesis 135
RUNX1/CBFbeta Structure 135
RUNX Proteins in Transcriptional Activation 135
RUNX Proteins in Transcriptional Repression 137
RUNX1 and CBFbeta Mutations in Leukemia Pathogenesis 138
AML Associated with the t(8 21) Translocation
The t(12 21) Translocation in Acute Leukemia
Inv(16) and t(16 16) in Acute Myeloid Leukemia
Alternative Mechanisms of RUNX Dysfunction in Leukemogenesis 145
Conclusions 146
References 146
Acute Myeloid Leukemia with Mutated Nucleophosmin (NPM1): Molecular, Pathological, and Clinical Features 154
Introduction 154
Structure of Nucleophosmin Protein 155
Phosphorylation of NPM1 Protein 157
Expression of NPM1 Protein 157
Functions of the NPM1 Protein 159
Regulation of Ribosome Biogenesis 159
Control of Centrosome Duplication 159
Control of p53 Activity and Stability 160
Interaction of NPM1 with the Oncosuppressor ARF 160
NPM1 Acts as an Oncogene and Oncosuppressor 161
AML with Mutated NPM1 161
General Characteristics of NPM1 Mutations 161
Aberrant Cytoplasmic Location of NPM1 Mutants 163
Diagnosis of AML with Mutated NPM1 163
Morphological Features and Immunophenotype of AML with Mutated NPM1 164
Clinical Features of AML with Mutated NPM1 166
Unsolved Issues and Future Directions 167
References 168
MicroRNAs: New Players in AML Pathogenesis 174
MicroRNAs: Biogenesis and Function 174
MiRNA in Hematopoiesis 176
MicroRNAs in Acute Myelogenous Leukemia 180
Concluding Remarks 183
References 184
Murine Models of Human Acute Myeloid Leukemia 187
Introduction: Strategies for Modeling Human AML in Mice 187
Xenotransplantation 188
Retroviral Transduction/Transplantation 190
Transgenesis 192
Modeling ‘‘Second Hits’’ 193
Chemical Mutagenesis 194
Insertional Mutagenesis 195
Radiation-Induced mutagenesis 195
Conclusions 196
References 196
Apoptosis in Leukemias: Regulation and Therapeutic Targeting 201
Introduction: Apoptosis pathways 201
The Extrinsic Pathway in Leukemia 204
The Intrinsic Pathway in Leukemia 204
Endogenous Inhibitors of Caspase Activity 206
Caspase-Independent Cell Death: The Role of Apoptosis-Inducing Factor (AIF) 207
Targeting the p53 Pathway to Induce Apoptosis in Leukemia 208
Targeting the Bcl-2 Rheostat to Induce Apoptosis in Leukemia 210
Targeting XIAP to Potentiate Apoptosis in Leukemia 213
Conclusions 213
References 215
Acute Promyelocytic Leukemia: A Paradigm for Differentiation Therapy 222
Clinical Features of Acute Promyelocytic Leukemia 223
Molecular Pathogenesis of APL 223
Mechanisms Underlying ATRA Response in APL 227
Mechanism of ATO Activity in APL 228
Establishment of ATRA in the Treatment of APL 230
Early Experience with ATRA as Single-Agent Therapy 230
‘‘Differentiation Syndrome’’ - The ‘‘Downside’’ of Differentiation Therapy 230
Optimizing ATRA Therapy to Improve Outcome in APL 231
Experience with Arsenic Compounds in the Management of APL 231
The Future of Differentiation Therapy in APL and Beyond 233
References 234
Immunotherapy of AML 239
Introduction: Biology of Anti-leukemia Immunity 239
Cellular Therapy 240
Hematopoietic Stem Cell Transplant (HSCT) 240
Donor Lymphocyte Infusion (DLI) 241
Selective T-Cell Therapy 243
Natural Killer Cells 245
NKT Cells 246
Antibodies 246
Cytokines 247
Vaccine Therapy 247
WT1 248
PR1 249
RHAMM/CD168 249
Dendritic Cells (DCs)-Based Vaccines 250
Conclusion 250
References 250
Therapy of Acute Myelogenous Leukemia in Adults 258
Introduction 258
Risk Categories 258
Standard Induction and Post-remission Therapy for Adult AML 259
Impact of Quality of Remission on Survival 261
Risk Adapted Post-remission Treatment of Younger Adults with AML 261
Good-Risk Cytogenetics Leukemias 261
Intermediate-Risk AML 263
High-Risk AML 263
Treatment of Elderly Patient with AML 264
Post-remission Therapy for Elderly 266
Allogeneic Stem Cell Transplant in the Elderly 266
Salvage Treatment for AML in Adults 266
Treatment of Minimal Residual Disease 267
References 267
Subject Index 273