Molecular Pathology of Hematolymphoid Diseases (eBook)

Cherie H. Dunphy (Herausgeber)

eBook Download: PDF

2010 | 2010
XIX, 620 Seiten
Springer US (Verlag)
978-1-4419-5698-9 (ISBN)

Infos

The past two decades have seen an ever-accelerating growth in knowledge about molecular pathology of human diseases, which received a large boost with the sequencing of the human genome in 2003. Molecular diagnostics, molecular targeted therapy and genetic therapy, are now routine in many medical centers. The molecular field now impacts every field in medicine, whether clinical research or routine patient care. There is a great need for basic researchers to understand the potential clinical implications of their research whereas private practice clinicians of all types (general internal medicine and internal medicine specialists, me- cal oncologists, radiation oncologists, surgeons, pediatricians, family practitioners), clinical investigators, pathologists and medical laboratory directors and radiologists require a basic understanding of the fundam- tals of molecular pathogenesis, diagnosis, and treatment for their patients. Traditional textbooks in molecular biology deal with basic science and are not readily applicable to the medical setting. Most medical textbooks that include a mention of molecular pathology in the clinical s- ting are limited in scope and assume that the reader already has a working knowledge of the basic science of molecular biology. Other texts emphasize technology and testing procedures without integrating the clinical perspective. There is an urgent need for a text that fills the gap between basic science books and clinical practice. In the Molecular Pathology Library series, the basic science and the technology is integrated with the medical perspective and clinical application.

Inhalt

Molecular pathology Library seriesPhilip T. Cagle, MD, Series Editor 1
Series Preface 4
Contributors 8
1 14
Molecular Oncogenesis 14
Introduction 14
The Initiation and Maintenance of Oncogenic Programs: Genetic and Epigenetic Changes 14
Types of Genetic Changes in Hematolymphoid Neoplasms 14
Genetic Changes in Leukemia and Myeloid Disorders 15
Multistep Pathogenesis and the Cooperativity of Genetic Alterations 15
Proliferation and/or Survival Signals 15
Block of Differentiation 17
Epigenetic Changes and Their Impact on Leukemogenesis 18
The Involvement of Stem Cells and Stem Cell Characteristics in Leukemia 19
Therapies Targeting Leukemia-Specific Molecular Alterations 19
Oncogenesis of Malignant Lymphoma 20
Programmed Genetic Changes of Antigen Receptor Genes during Normal Lymphocyte Development 20
Generation of Antibody Diversity and B-Cell Lymphoma Development 20
Primary Immunoglobulin Gene Rearrangement 20
Oncogene Activation Caused by Illegitimate Recombination during Immunoglobulin Gene Rearrangement 21
IGH Translocations may Often be Detected in the Absence of Clinical Disease 21
The Germinal Center Reaction and Lymphomagenesis 22
Mutational Analysis of IGH Genes Captures the History of Malignant B-Cell Clones 22
Genetic Alterations in Peripheral T-Cell Lymphoma 23
Oncogenes and Oncogenic Pathways in Malignant Lymphoma 24
The Properties of the Activated Oncogene Determine the Biologic and Clinical Behavior of Lymphomas 24
BCL-2 24
CCND1 (Cyclin D1) 24
C-MYC 25
BCL-6 25
Deregulation of the NF-kB Pathway 25
Tumor Suppressor Genes in Lymphoma 25
Inhibition of Death Receptor Signaling 25
MicroRNA Deregulation 26
Infectious Agents Contributing to Lymphomagenesis 26
Conclusion 26
References 26
2 31
Genetic Predispositions for Hematologic and Lymphoid Disorders 31
Introduction 31
Neurofibromatosis 31
Molecular Pathogenesis of NF1 33
Hematolymphoid Disorders Associated with NF1 33
Tests for NF1 34
Noonan Syndrome 34
Molecular Pathogenesis of NS 34
Hematolymphoid Disorders Associated with NS 35
Tests for NS 36
Fanconi Anemia 36
Molecular Pathogenesis of FA 37
Hematologic Disorders Associated with FA 37
Pathogenesis of Neoplasms Associated with FA 39
Tests for FA 39
Bloom’s Syndrome 39
Molecular Pathogenesis of BS 39
Hematolymphoid Disorders Associated with BS 40
Tests for BS 41
Nijmegen Breakage Syndrome 41
Molecular Pathogenesis of NBS 41
Hematolymphoid Disorders Associated with NBS 41
Tests for NBS 42
Ataxia-Telangiectasia 42
Molecular Pathogenesis of AT 43
Hematolymphoid Disorders Associated with AT 43
Tests for AT 43
Dyskeratosis Congenita 44
Molecular Pathogenesis of DC 44
Hematolymphoid Disorders Associated with DC 46
Tests for DC 46
Shwachman–Diamond Syndrome 46
Molecular Pathogenesis of SDS 46
Hematopoietic Disorders Associated with SDS 47
Tests for SDS 47
Diamond–Blackfan Anemia 48
Molecular Pathogenesis of DBA 48
Hematopoietic Disorders Associated with DBA 49
Tests for DBA 49
Primary Immune Deficiency Disorders 49
X-Linked Lymphoproliferative Disorder (Also See Chap. 38) 50
Molecular Pathogenesis of XLP 50
Testing for XLP 51
Hyper-IgM Syndromes (Also See Chap. 38) 51
Pathogenesis of HIGM 52
Hematolymphoid Disorders Associated with HIGM 53
Tests for HIGM 54
Hyper-IgE Syndromes 54
Pathogenesis of HIES 54
Hematolymphoid Disorders Associated with HIES 54
Common Variable Immune Deficiency (Also See Chap. 38) 54
Molecular Pathogenesis of CVID 55
Hematolymphoid Disorders Associated with CVID 55
Tests for CVID 56
Wiskott–Aldrich Syndrome (Also See Chap. 39) 56
Hematolymphoid Disorders Associated with WAS 56
Tests for WAS 57
Autoimmune Lymphoproliferative Syndrome (Also See Chap. 38) 57
Molecular Pathogenesis of ALPS 57
Hematolymphoid Disorders Associated with ALPS 58
Tests for ALPS 58
Congenital Neutropenia Syndromes 58
Molecular Pathogenesis of Congenital Neutropenia Syndromes 58
Hematologic Neoplasias Associated with Congenital Neutropenia Syndromes 60
Tests for Congenital Neutropenia Syndromes 60
Summary 60
References 60
3 75
Prognostic Markers 75
Introduction 75
Chronic Lymphocytic Leukemia (Also See Chap..16) 75
Immunoglobulin Variable Gene Mutation Analysis 75
Genomics 76
Multiple Myeloma (Also See Chap..19) 77
Acute Myeloid Leukemia (Also See Chaps..34 and 35) 77
FMS-Related Tyrosine Kinase 3 (Also See Chap..35) 77
Nucleophosmin (Also See Chap..35) 77
Non-Hodgkin Lymphoma 78
Diffuse Large B-Cell Lymphoma (Also See Chap..22) 78
Marginal Zone Lymphoma (Also See Chap..17) 79
References 79
4 83
Cancer Stem Cells: Potential Targets for Molecular Medicine 83
Introduction 83
The Cancer Stem Cell Hypothesis 83
Cancer Stem Cells, Defined 83
Historical Perspective 83
The Biology of Cancer Stem Cells 84
Cancer Stem Cell Identification 84
Functional Identification 84
In Vivo CSC Isolation Methods 84
In Vitro CSC Assays 84
Molecular Methods 84
Phenotypic Identification 85
Cell Surface Markers 85
In Vivo Monitoring of CSC 85
Molecular Pathogenesis of Cancer Stem Cells 85
Pathogenesis of CSC in Blast Crisis of CML (Also See Chap. 30) 86
Molecular Changes Contributing to CSC Propagation in Blast Crisis of CML 86
Clinical Implications of Cancer Stem Cells 86
CSC in Cancer Diagnosis, Prognosis, and Monitoring 87
Cellular and Molecular Assays 87
Cellular and Molecular Imaging 87
CSC-Directed Cancer Treatment 88
References 88
5 91
Gene Therapy for Leukemia and Lymphoma 91
Introduction 91
Viral Vectors Used for Gene Therapy 91
Gene Targeting to Destroy Tumor Cells Directly 92
Tumor Suppressor Gene Therapy 92
Suicide Gene Therapy 92
RNA Interference 93
Gene Transfer to Enhance Immune Responses to Tumor Cells 94
Gene Transfer of Immunostimulating Cytokines 94
Gene Transfer of Costimulating Molecules 94
Modification of T-Cell Function by Gene Transfer 95
Chimeric T-Cell Receptors 95
Gene Transfer of TCR for Retargeting 96
Gene Transfer of Protective Genes 96
Conclusion and Future Directions 96
References 97
6 100
Chemical and Environmental Agents (Including Chemotherapeutic Agents and Immunosuppression) 100
Introduction 100
Ionizing Radiation 100
Childhood Studies 100
Background Radiation (Natural and Man-Made) 100
Parental Occupational Exposures 100
Parental Diagnostic Exposures 101
Childhood Diagnostic Exposures 101
Adult Studies (Table 6.1) 101
Background Radiation (Natural and Man-Made) 101
Occupational Exposures 101
Diagnostic/Treatment Exposures 101
Electromagnetic Fields 101
Childhood Studies 102
Direct Childhood Exposures 102
Parental Occupational Exposures 102
Adult Studies (Table 6.2) 102
Residential Exposures 102
Occupational Exposures 102
Chemical Exposures 102
Childhood Studies 102
Pesticides and Fungicides 102
Solvents, Benzene and Other Hydrocarbons 103
Adult Studies (Table 6.3) 103
Pesticides and Fungicides 103
Solvents, Benzene and Other Hydrocarbons 103
Smoking 105
Childhood Studies 105
Parental Smoking 105
Adult Studies (Table 6.4) 105
Alcohol 106
Childhood Studies 106
Parental Alcohol Consumption 106
Adult Studies (Table 6.5) 106
Diet, Vitamin, and Folate Supplementation 107
Childhood Studies 107
Adult Studies (Table 6.6) 108
Drinking Water 108
Child Studies 108
Adult Studies 108
Immunosuppression and Viruses 108
Viruses (Also See Chap. 7) 108
Child Studies 108
Adult Studies (Table 6.7) 109
Transplantation 109
Arthritis 110
Chemotherapeutic Agents 110
Discussion 110
References 110
7 116
Viral Oncogenesis 116
Introduction 116
Do In Vitro Models Reflect In Vivo Effects? 116
Epstein–Barr Virus 117
Histochemical Assays for EBV 118
Human Herpes Virus 8/Kaposi’s Sarcoma-Associated Herpes Virus 118
Human T-Lymphotropic Virus 121
Hepatitis C Virus 122
Simian Vacuolating Virus 40 123
Measles Paramyxovirus 123
Conclusion 124
References 124
8 127
Techniques to Determine Clonality in Hematolymphoid Malignancies 127
Introduction 127
Cancer as Clonal Process 127
X Inactivation 127
Lymphomas 128
Lymphoid Development 128
B Cell Clonality 129
Light Chain Restriction 129
Molecular Methods for Determining B Cell Clonality 129
T Cell Clonality 131
T Cell Receptor Restriction 131
Molecular Methods for Determining T Cell Clonality 131
Natural Killer Cell Clonality 132
Other Clonal Markers in Lymphoid Malignancies 132
Translocations Resulting in Overexpression of Growth Regulatory Genes 132
Translocations Resulting in Production of a Novel Growth-Stimulating Protein 133
Clonal Viral Integration 133
Myeloid Stem Cell Neoplasms 133
Clonal Recurrent Chromosomal Translocations 133
Gene Mutations in Leukemia (Also see Chap. 35 on Acute Myeloid Leukemias with Normal Cytogenetics) 133
JAK2 Mutation in Myeloproliferative Neoplasms (Also see Chap. 31 on Non-CML Myeloproliferative Neoplasms) 134
Array-Based Techniques that may Determine Clonality 134
Summary 135
References 135
9 137
Techniques to Detect Defining Chromosomal Translocations/Abnormalities 137
Introduction 137
Conventional (Routine) Cytogenetics 137
Fluorescence In-Situ Hybridization (FISH) 138
Cytogenetic Abnormalities in Hematolymphoid Malignancies 140
Acute Myeloid Leukemias (AML) 140
World Health Organization (WHO): AML with Recurrent Cytogenetic Translocationst(8 21)
FISH for t(15 17)
FISH for Chromosome 16 Rearrangements 142
11q23 Rearrangements 143
FISH for 11q23 (MLL) 143
Abnormalities Seen in AML with Multi-Lineage Dysplasia 143
Secondary or Therapy-Related AML 143
Chronic Myeloid Leukemia (CML): t(9 22)(q34q11.2)143
Myelodysplastic Syndromes (MDS) 144
5q Syndrome 144
Monosomy 7/7q— 144
Other Abnormalities in MDS 144
Acute Lymphoblastic Leukemia (ALL) 144
Cytogenetic Abnormalities Seen in T-ALL 144
Cytogenetic Abnormalities Seen in Pre B-ALL 145
Numerical Abnormalities in Pre-B-ALL 145
Structural Rearrangements 145
Translocations Associated with Pre B ALL 145
t(12 21)(p13q22)145
Myeloid Lymphoid Leukemia (MLL) Rearrangements 145
t(4 11)(q21q23)146
t(1 19)(q23p13.3)146
t(9 22)(q34q11.2)146
Pediatric ALL 146
Adult ALL 146
Non-Hodgkin Lymphomas (NHL) 146
Follicular Lymphoma and Diffuse Large B-Cell Lymphomas with t(14 18)
Mantle Cell Lymphoma with t(11 14)
Burkitt Lymphoma with t(8 14) and Other Burkitt Translocations147
FISH for t(8 14) and Other Burkitt Translocations147
Anaplastic Large Cell Lymphoma 147
FISH for ALK Rearrangements 147
Splenic Marginal Zone Lymphoma 147
Mucosa-Associated Lymphoid Tissue Lymphoma (MALT) 147
Multiple Myeloma (Plasma cell myeloma) 147
FISH Studies for Multiple Myeloma 148
Spectral Karyotyping 148
DNA Microarray 148
Polymerase Chain Reaction 149
Reverse Transcriptase PCR (RT-PCR) 150
Real-Time Quantitative PCR 150
BCR-ABL1 [t(9 22)]
Other Translocations 153
Immunohistochemistry 154
Acute Myeloid Leukemias 154
PAX 5 [t(8 21)]
Non-Hodgkin Lymphomas 154
BCL-2 [t(14 18)]
ALK-1 [t(2 5)]
Cyclin D1 156
References 156
10 161
Molecular Techniques to Detect Disease and Response to Therapy: Minimal Residual Disease 161
Overview 161
Molecular Approaches to MRD Monitoring 161
Patient Samples 161
Targets 161
Antigen Receptor Rearrangements in the Immunoglobulin Super Family 161
Chromosomal Translocations Resulting in Fusion-Gene Transcripts Followed by RNA Analysis 162
Chromosomal Aberrations Resulting in a Fusion Gene Followed with DNA 162
Additional Considerations in the Use of RNA or DNA 162
“Point” Mutations 163
Aberrant Gene Expression 163
Other Techniques to Monitor MRD 163
Karyotype and FISH 163
Flow Cytometry 163
Microarrays 163
Transcription-Mediated Amplification (TMA)-Hybridization Protection Assay (HPA) 163
Quantitative PCR and RT-PCR 164
Quantitative PCR Techniques (Nested, Competitive, Real-Time) 164
RQ-PCR Assay Design 164
Samples 164
RNA Extraction 164
Reverse Transcription (RT) 164
RQ-PCR Amplification 165
Quantitation, Standard Curve Method 165
Quantitation, DDCT Method 165
Data Analysis and Reporting of Results 166
Units of Measurement and Assay Standardization 167
Sensitivity, Specificity, and Precision 168
Controls/Normalizing Genes 168
Assay Validation 168
Working with Clinicians 169
Ensuring Quality 169
Future Directions 169
References 169
11 173
Detection of Resistance to Therapy in Hematolymphoid Neoplasms 173
Introduction 173
Resistance to Targeted Tyrosine Kinase Inhibitors 173
Resistance to Inhibitors of BCR-ABL 173
Mutations in the ABL Tyrosine Kinase Domain 173
Amplification of the BCR-ABL Fusion Gene 174
BCR-ABL Independent Resistance: Downstream Targets 174
KIT Mutation and Imatinib Response 175
FLT3 IN AML 175
Multidrug Resistance 175
P-glycoprotein (MDR-1) 175
Detection of MDR in Hematologic Malignancies 176
Other Multidrug Resistance Proteins 176
Other Molecular Mechanisms of Resistance 176
Microarray Analysis 176
References 176
12 180
Monitoring Engraftment of Bone Marrow Transplant by DNA Fingerprinting 180
Introduction 180
A Brief History of DNA Fingerprinting Methods 180
Past 180
Present 180
Future 181
Monitoring Engraftment of Bone Marrow Transplant 181
Microsatellite Markers 181
Technical Considerations 181
Identification of Informative Markers 181
Quantitative Calculations 182
Sensitivity 182
Clinical Considerations 182
Enriched Populations 182
Chromosomal Abnormalities 182
Impact on Future Genetic Testing 182
References 182
13 184
Gene Expression Profiling 184
Introduction 184
Techniques of Gene Expression Profiling 184
Supervised Gene Expression Profiling 184
Unsupervised Gene Expression Profiling 184
Usefulness of Ready-Made Macroarrays 185
Practical Applications in Diagnostic Hematopathology 185
Prognostic Factors in Chronic Lymphocytic Leukemia and Correlation with Practical Clinical Applicability (See Table 13.1) 185
IgVH Mutational Status 185
ZAP70 186
Methods of Detection of ZAP70 Expression 186
Discordance Between IgVH Mutational Status and ZAP70 Expression 186
Diagnosis of Mantle Cell Lymphoma 187
Diagnosis of Hairy Cell Leukemia 187
Grade and Disease Aggressiveness in Follicular Lymphoma 188
Subgrouping Diffuse Large B-Cell Lymphoma and Correlation with Immunohistochemical Markers 188
Differentiation of Classical Hodgkin Lymphoma from Lymphocyte-Predominant Hodgkin Lymphoma and From Diffuse Large B-Cell Lymph 189
Class Assignment of Pediatric Precursor B Lymphoblastic Leukemia 189
Distinctive Gene Expression Signatures of Precursor T-Cell Lymphoblastic Leukemia and Correlation with Stage of Differentiat 190
Association of Distinct Gene Expression Profiles with Acute Myeloid Leukemias with Recurring and Complex Abnormalities and Cor 190
AMLS with FLT3 Length Mutation 194
Summary 195
References 195
14 197
Proteomics of Human Malignant Lymphoma 197
Introduction 197
Biological Samples for Proteomics 197
General Strategy for Proteomics 197
Protein Microarrays 197
Mass Spectrometry-Based Proteomics 198
Peptide Sequencing by MS/MS 198
Quantitative Proteomics 198
Proteomic Studies of Human Malignant Lymphoma 199
Proteomic Studies of B-Cell Lymphomas 199
Analysis of Interacting Partners of B-Cell Lymphoma Oncogenes 200
Proteomic Analysis of Follicular Lymphoma Transformation 201
Proteomic Consequences of Signaling Pathway Inhibition 201
Global Protein Profiling Studies 201
Burkitt Lymphoma 201
Hodgkin Lymphoma 202
Proteomic Studies for Identification of Potential Lymphoma Biomarkers 203
Protein Identification From FFPE Cells 204
Proteomic Studies of Anaplastic Large Cell Lymphoma 204
Global Profiling of ALCL Proteome 205
Identification of ALK Interactome 205
Proteomic Changes Induced by HSP90 205
Conclusions and Future Directions 206
References 206
15 209
Mouse Models of Hematolymphoid Malignancies 209
Introduction 209
Hematopoiesis 209
Characterization of Mouse Models 210
Clinical Pathology 210
Complete Blood Count 210
Biochemical Parameters 211
Anatomic Pathology 211
Macroscopic Evaluation 211
Microscopic Evaluation 211
Ancillary Testing 211
Lymphoid Neoplasms 211
Nonlymphoid Neoplasms 212
Myeloid Leukemia 212
Erythroid Leukemia 212
Conclusion 213
References 213
16 216
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 216
Introduction 216
Familial Predisposition 216
Cytogenetic Features 216
Immunoglobulin Genes 218
Epigenetic Factors 219
Clinical Implications 220
References 220
17 226
Marginal Zone B-Cell Lymphoma 226
Introduction 226
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma) 226
Definition 226
Clinical Features 226
Morphology and Immunophenotype 227
Prognosis and Predictive Factors 227
Cytogenetic and Molecular Genetic Features 227
t(11 18)(q21q21)/API2-MALT1227
t(14 18)(q32q21)/IGH-MALT1228
t(1 14)(p22q32)/BCL10-IgH228
The t(11 18), t(1418), and t(114) Activate the NF-kB Pathway228
t(3 14)(p14q32)/Forkhead Box P1-IGH229
Translocation-Negative Cases 229
Differential Diagnosis 230
Immunoproliferative Small Intestinal Disease 230
Definition 230
Clinical Features 230
Morphology and Immunophenotype 230
Cytogenetic and Molecular Genetic Features 230
Nodal Marginal Zone Lymphoma 230
Definition 230
Clinical Features 230
Morphology and Immunophenotype 231
Differential Diagnosis 231
Cytogenetic and Molecular Genetic Features 231
Pediatric Nodal Marginal Zone Lymphoma 231
Splenic B-Cell Marginal Zone Lymphoma 231
Definition 231
Clinical Features 231
Prognosis and Predictive Factors 232
Morphology and Immunophenotype 232
Differential Diagnosis 232
Cytogenetic and Molecular Genetic Features 232
References 233
18 237
Lymphoplasmacytic Lymphoma 237
Introduction 237
Epidemiology 238
Cell of Origin 238
Cytogenetics 238
Molecular Genetics 239
Proteinomics 239
Activated Signaling Pathways 239
Differential Diagnosis 239
Conclusions 241
References 241
19 244
Molecular Pathology of Plasma Cell Neoplasms 244
Introduction 244
Techniques for the Assessment of Molecular Abnormalities in Plasma Cell Neoplasms 244
Metaphase Cytogenetic Studies 244
Fluorescence In Situ Hybridization Analysis 244
Immunohistochemistry 246
Array-Based Genotyping 246
Clinically Significant Molecular Abnormalities in Plasma Cell Myeloma 246
Chromosome 13 Abnormalities 246
Del(17p) and p53 Abnormalities 246
Immunoglobulin Heavy Chain (14q32) Translocations 247
t(11 14)(q13q32) IGH/CCND1247
t(4 14)(p16q32) MMSET/IGH247
t(14 16)(q32q23) IGH/CMAF247
Other IGH Translocations 248
Other Chromosomal Abnormalities 248
A Practical Approach to Molecular Evaluation of Plasma Cell Myeloma 248
References 248
20 251
The Roles of Molecular Techniques in the Diagnosis and Management of Follicular Lymphoma 251
Introduction 251
Practical Aspects of Molecular Genetic Testing in the Diagnosis and Management of Follicular Lymphoma 251
Molecular Genetic Tests Available for FL 252
The Molecular Pathogenesis of FL and Its Impact on Molecular Diagnostics 252
What Goes Wrong to Make Follicular Lymphoma? The “First” Hit 253
The “Second” Hit 253
Immunoglobulin Genes in FL 254
Molecular Genetic Analysis by Gene Expression Profiling Largely Reflects the Microenvironment (Also See Chap. 13) 255
The “Third Hit”: Mechanisms of Large Cell Transformation 255
Molecular Variants of FL 255
Implications of Pathogenesis for Molecular Assays 255
Clonality Detection by IG PCR 255
Detection of BCL2 Translocations 256
References 256
21 258
Mantle Cell Lymphoma 258
Introduction 258
Epidemiology 258
Clinical Presentation 258
Histopathology 258
Immunophenotype 258
Pathogenesis 259
Initial Oncogenic Event 259
Secondary Genetic Alterations 259
Pathway Dysregulations in MCL 260
Dysregulations in Cell Cycle Control 260
Dysregulations in DNA Damage Response Pathway 260
Dysregulations in Cell Survival Pathway 261
Dysregulations in MicroRNA-17–92 Expression 261
Molecular Diagnosis 262
Proteomics and Antibody-Based Protein Array 262
Prognosis 263
Therapy 263
Summary 263
References 263
22 267
Diffuse Large B-Cell Lymphomas 267
Introduction 267
Distinction of De Novo DLBCL from DLBCL of Follicular Origin 267
Subgrouping of DLBCL and Prediction of Prognosis 267
Correlation of Immunohistochemical Analyses with GEP Data in DLBCL 270
Correlation of GEP Data and Immunohistochemical Patterns with Cytogenetic Abnormalities in DLBCL 270
Future Directions 271
Differentiation from Burkitt Lymphoma 271
Differentiation of De Novo DLBCL, De Novo CD5+ DLBCL, and Mantle Cell Lymphoma 272
AIDS-Related DLBCL 273
Cutaneous Large B-Cell Lymphoma 274
Primary Mediastinal Large B-cell Lymphoma 274
Summary 275
References 275
23 277
The Molecular Pathology of Burkitt Lymphoma 277
History and Clinical Features of Burkitt Lymphoma 277
EBV and Burkitt Lymphoma (Also See Chap..7) 278
Myc and Burkitt Lymphoma 279
Diagnosis of Burkitt Lymphoma 280
Microarray Profiling 282
Therapy of Burkitt Lymphoma/Leukemia 282
New Therapeutic Agents 283
References 283
24 286
Precursor B-Cell Acute Lymphoblastic Leukemia 286
Introduction 286
Abnormalities of Chromosome Number 287
High Hyperdiploidy 287
Hypodiploidy 287
Frequent Structural Chromosome Abnoramlities 288
t(12 21)(p13q22) ETV6-RUNX1288
Molecular Characterization of the ETV6-RUNX1 Fusion (Figure 24.1a)74 288
Prognostic Significance of ETV6-RUNX1 288
ETV6-RUNX1 in Relapsed Pediatric ALL 290
Philadelphia Chromosome: t(9 22)(q34q11.2)BCR-ABL1290
Molecular Characterization of the BCR-ABL1 Fusion (Figure 24.1b)74 290
Prognostic Significance of BCR-ABL1 290
New Therapies for BCR-ABL1+ ALL 290
Rearrangements of the MLL Gene at 11q23 291
Molecular Description of MLL, Fusion Partners, and the MLL Fusion Genes (Figure 24.1c)74 291
Prognostic Significance of MLL Rearrangements 292
Transplantation Therapy for ALL with MLL Rearrangements 292
t(1 19)(q23p13.3)TCF3-PBX1292
Molecular Description of the TCF3-PBX1 Fusion (Figure 24.1d)74 293
Prognostic Significance of TCF3-PBX1 293
Abnormalities of Chromosome Arm 9p 293
Molecular Characterization of Gene Mutations and Deletions Mapping to 9p 293
Prognostic Significance of 9p Abnormalities 294
Intrachromosomal Amplification of Chromosome 21 and RUNX1 Gene Amplification 294
Detection of Minimal Residual Disease by Molecular Methods in Patients with Chromosomal Abnormalities 294
B-Precursor Lymphoblastic Lymphoma 295
Conclusions and Future Directions 295
References 295
25 307
Molecular Genetics of Mature T/NK Neoplasms 307
Introduction 307
Diagnosis of T/NK Neoplasms 307
Mycosis Fungoides 309
Anaplastic Large Cell Lymphoma, ALK-Positive 309
Angioimmunoblastic T Cell Lymphoma 311
Natural Killer/T Cell Neoplasms 313
Extranodal Peripheral T Cell Lymphomas 315
T-Prolymphocytic Leukemia 317
Adult T Cell Leukemia/Lymphoma 318
T-Large Granular Lymphocyte Leukemia 319
Therapeutic Implications of T-Cell Receptors and Molecular Pathways 320
References 320
26 326
Precursor T-Cell Neoplasms 326
Introduction 326
Activating Mutations in the NOTCH1 Signaling Pathway 327
Aberrant Expression of Transcription Factor Oncogenes 328
Basic Helix-Loop-Helix Transcription Factor Oncogenes TAL1, TAL2, LYL1, and BHLHB1 328
LIM Only Domain Factors LM01 and LM02 329
Homeobox Transcription Factors TLX1, TLX3 and HOXA9 329
MYB 330
MYC 330
Transcription Factor Fusion Oncogenes 330
MLL-MLLT1 331
PICALM-MLLT10 (CALM-AF10) 331
SET-NUP214 331
NUP98 Fusion Oncogenes 331
Aberrant Activation of Tyrosine Kinase Oncoproteins 332
NUP214-ABL and EML1-ABL 332
JAK1 Mutations 332
FLT3 Mutations 333
LCK Translocation and Overexpression 333
RAS Gene Mutations and Loss of NF1 333
Mutational Loss of PTEN 333
Alterations in Cyclin-Dependent Kinase Inhibitors and Cyclin D2 Overexpression 334
Clinical Implications for Therapy Stratification and Molecularly Targeted Drugs 334
References 335
27 344
Classical Hodgkin Lymphoma and Nodular Lymphocyte Predominant Hodgkin Lymphoma 344
Background 344
Hodgkin “Disease” Is a B-Cell “Lymphoma” 344
Oncogenic Events in Classical Hodgkin Lymphoma 346
Mutations 346
Chromosomal Gains/Genomic Amplifications 346
Chromosomal Losses 346
Epigenetic Events 347
Translocations 347
microRNAs (miRNAs) 347
Gene Expression Profiling 347
Proteomics (Also See Chap. 14) 347
Genetic Predisposition 347
Role of EBV (Also See Chap. 7) 348
The Peculiar Phenotype of HRS Cells 348
Disrupted Cellular Pathways 350
Nodular Lymphocyte Predominant Hodgkin Lymphoma 351
Summary 351
References 351
28 356
Posttransplant Lymphoproliferative Disorder 356
Introduction 356
Clinical Setting 356
Histopathology 356
Clonality and Clonal Evolution 357
Mechanisms of Viral Lymphomagenesis 358
Host Chromosomal Genetic Alteration 359
EBV-Negative PTLD 359
Blood Tests to Diagnose, Predict and Monitor PTLD 359
Therapy 360
Conclusion 360
References 360
29 363
AIDS-Related Lymphomas 363
Introduction 363
Oncogenic Viruses (Also See Chap. 7) 363
Epstein–Barr Virus (EBV HHV4)363
Latency Membrane Protein-1 (LMP1) 363
Latency Membrane Protein-2 (LMP2A) 364
EBV Nuclear Antigen 2 (EBNA2) 364
Kaposi Sarcoma Herpesvirus (KSHV HHV8)364
Latent Nuclear Antigen-1 (LANA LNA-1 Open Reading Frame [ORF] 73)364
Viral Cyclin (v-Cyclin ORF 72)364
Viral Fas-Associated Death Domain Interleukin-1b-Converting Enzyme Inhibitory Protein (v-FLIP ORF71/K13)364
Viral Interleukin 6 (v-IL-6 K2)364
Viral Interferon Regulatory Factor (v-IRF3 LANA2 ORFK10.5)364
Classification of AIDS-Related Lymphomas 364
Lymphomas Also Occurring in Immunocompetent Individuals 365
Burkitt Lymphoma (BL) 365
Diffuse Large B-Cell Lymphoma (DLBCL) 368
Lymphomas Occurring More Specifically in HIV-Positive Patients 371
Primary Effusion Lymphoma (PEL) and Extra-Cavitary PEL (EC-PEL) 372
Large B-Cell Lymphoma Arising in HHV8 (KSHV)-Associated Multicentric Castleman Disease (MCD) 374
Plasmablastic Lymphoma 374
Lymphomas Occurring in Other Immunodeficient States 374
Polymorphic Lymphoid Proliferations 374
References 375
30 382
Chronic Myelogenous Leukemia 382
Introduction 382
Diagnostic Criteria 382
Clinicopathologic Features 382
Standard Therapy 384
Molecular Monitoring of CML 384
Routine Monitoring Algorithms 384
Assay Design and Quality Control Considerations for BCR-ABL RQ-PCR 385
Molecular Mechanisms of Therapy Resistance in CML (Also See Chap. 11) 385
Primary Imatinib Resistance 385
Secondary Imatinib Resistance and Blast Transformation 386
ABL KD Mutation 386
Clonal Evolution 387
References 387
31 390
Molecular Pathogenesis of Nonchronic Myeloid Leukemia Myeloproliferative Neoplasms 390
Introduction 390
Cytogenetics of Nonchronic Myeloid Leukemia Myeloproliferative Neoplasms 391
Molecular Pathways Involving MPN 392
JAK2V617F Mutations 392
Other JAK Mutations 393
MPLW515 Mutations 393
Expression Profiling Findings in MPNS 394
Molecular-Targeted Therapy 395
References 395
32 399
Molecular Pathology of Myelodysplastic/Myeloproliferative Neoplasms, Myeloid and Lymphoid Neoplasms with Eosinophilia and Abn 399
Myelodysplastic/Myeloproliferative Neoplasms: General Aspects 399
Chronic Myelomonocytic Leukemia 399
Atypical Chronic Myeloid Leukemia, BCR–ABL1 Negative 400
Juvenile Myelomonocytic Leukemia 401
Refractory Anemia with Ring Sideroblasts and Marked Thrombocytosis 402
Other Unclassifiable Myelodysplastic/Myeloproliferative Neoplasms 403
Myeloid and Lymphoid Neoplasms Associated with Eosinophilia and Abnormalities of PDGFRA, PDGFRB, and FGFR1 Rearrangement: Ge 403
Myeloid and Lymphoid Neoplasms Associated with PDGFRA Rearrangement 403
Myeloid Neoplasms Associated with PDGFRB Rearrangement 404
Myeloid and Lymphoid Neoplasms Associated with FGFR1 Rearrangement 404
Mastocytosis 405
Summary 405
References 407
33 411
Molecular Pathogenesis of Myelodysplastic Syndromes 411
Introduction 411
MDS Associated with Recurrent Cytogenetic Abnormalities and Molecular Genetic Lesions 413
Gene Expression Profiling Findings in MDS 414
Single Nucleotide Polymorphisms Profiling Findings in MDS 414
Cytokine Profiling Findings in MDS 415
Molecular Pathways Involved in MDS 415
Oncogenes 415
Cell Cycle Regulatory Genes 416
Apoptotic Genes 416
Growth Factor and Angiogenesis Genes 416
Receptor Tyrosine Kinase Genes 416
Epigenomic Changes in MDS 416
Methylation 416
Histone Deacetylation 416
Targeted Therapies 417
References 417
34 422
Acute Myeloid Leukemias with Recurrent Cytogenetic Abnormalities 422
Introduction 422
Epidemiology 422
Clinical Features 422
Examination of the Peripheral Blood and Bone Marrow 423
Morphologic Features 423
Cytochemical Features 424
Immunophenotyping Using Flow Cytometry 424
Immunohistochemical Analyses 425
Electron Microscopy 425
Cytogenetic and Molecular Markers 425
Gene Expression Profiling 425
Prognostic Indicators 425
Molecular Abnormalities in AML 426
Molecular Mechanisms of AML 426
AML with Recurrent Genetic Abnormalities 427
AML with t(8 21)(q22q22.3) RUNX1–RUNX1T1 (AML1/ETO or RUNX1/MTG8)427
AML inv(16)(p13.1q22) or t(16 16)(p13.1q22) CBFb-MYH11428
Acute Promyelocytic Leukemia with t(15 17)(q22q21) PML/RARA, and Variants428
AML with t(9 11)(p22q23), MLLT3–MLL430
AML with t(6 9)(p23q34) DEK–NUP214430
AML with inv(3)(q21q26.2) or t(3 3)(q21q26.2) RPN1-EVI1431
AML (Megakaryoblastic) with t(1 22)(p13q13) RBM15-MKL1431
AML with Gene Mutations 432
Translocations in AML Not Included in AML with Recurrent Genetic Abnormality Category of WHO 2008 Classification 432
AML with 11q23 (MLL) Abnormalities Other than t(9 11)
AML with Other Translocations Involving 11q23 433
AML with 11q23 Rearrangements and Normal Conventional Cytogenetics or Trisomy 11 433
AML with inv(11)(p15q22) 433
AML with t(16 21)(p11q22)433
AML with t(12 22)(p13q11)434
AML with t(8 16)(p11p13)434
AML with t(3 21)(q26q22)434
AML with t(9 22)(q34q11)434
AML with t(7 11)(p15p15)435
References 435
35 442
Acute Myeloid Leukemias with Normal Cytogenetics 442
Introduction 442
Abnormalities Affecting Proliferation/Apoptosis of Leukemia Cells Directly 442
FLT3 Gene Mutations (Also See Chapter 11) 442
RAS Gene Mutations 443
Kit Gene Mutations 444
G-CSF Receptor Gene Mutations 444
NPM1 Gene Mutations 444
RB1 Gene Mutations 445
P53 Gene Mutations 445
STAT Activation 445
CXCR4 Overexpression 445
Antigen Receptor Gene Rearrangement 446
BAALC Gene 446
CEBPA Gene 446
ERG Gene 447
MN1 Gene 447
Other Prognostic Factors in Karyotypically Normal AML 447
Abnormalities Affecting Proliferation/Apoptosis of Leukemia Cells Directly 447
Osteoblasts 448
Leptin 448
Microvasculature 448
Conclusions 449
References 449
36 456
Acute Myeloid Leukemia with Myelodysplasia-Related Changes and Therapy-Related Acute Myeloid Leukemia 456
Introduction 456
Classification of AML 456
Dysplasia in Myeloid Cells 458
Detection of Dysplasia Using Flow Cytometric Immunophenotyping 458
Cytochemical Features of AML 458
Immunophenotype 458
Genetics and Molecular Markers 458
Gene Expression Profiling 460
DNA Methylation 461
Summary 461
References 462
37 465
Molecular Pathology of Hemoglobin and Erythrocyte Membrane Disorders 465
Introduction 465
Molecular Pathology of Hemoglobin Disorders 465
The Thalassemia Syndromes 466
Introduction 466
b Thalassemia Syndromes 467
Introduction 467
Molecular Pathology and Pathophysiology 467
Clinical Features and Therapy 467
b Thalassemia Major 467
b Thalassemia Intermedia 469
b Thalassemia Trait 469
db Thalassemia 469
HB E-b Thalassemia 469
Hemoglobin Lepore 469
Thalassemia Syndrome not Associated with a Globin Gene Mutation 470
a Thalassemia Syndromes 470
Molecular Pathology and Pathophysiology 470
Clinical Features and Therapy 471
a+ Thalassemia 471
a0 Thalassemia 471
Hb H Disease 471
HB Bart’s and Hydrops Fetalis 471
a Thalassemia Associated with Mental Retardation 471
Acquired Hb H Disease 472
Hb Constant Spring 472
Sickle Cell Disease 472
Introduction 472
Molecular Pathology and Pathophysiology 472
Clinical Features and Therapy 472
Sickle Cell Variants 473
Hb SC Disease 473
Sickle-b Thalassemia 473
Sickle Cell Trait 473
Other Sickle Cell Variants 474
Hereditary Persistence of Fetal Hemoglobin Syndromes 474
Unstable Hemoglobin Variants 474
Hemoglobin Variants with Altered Oxygen Affinity 475
Methemoglobinemias 475
Laboratory Evaluation and Diagnosis of Hemoglobinopathies 476
Complete Blood Count and Examination of a Blood Film 476
Sickle Solubility Test 476
Hemoglobin Electrophoresis at Alkaline pH 476
Hemoglobin Electrophoresis at Acid pH 476
Isoelectric Focusing 476
Capillary Electrophoresis 476
High-Performance Liquid Chromatography 477
Hb A2 Quantitation by Column Chromatography 477
Hb F Quantitation 477
z Globin Detection in a0 Thalassemia Carriers 477
DNA-Based Tests 477
Molecular Pathology of Erythrocyte Membrane Disorders 477
Hereditary Spherocytosis 477
Pathophysiology 477
History and Physical 478
Laboratory Testing 479
Peripheral Blood Smear 479
Blood Count and RBC Indices 479
Osmotic Fragility 480
Other Tests 480
Molecular Studies 480
Markers of Hemolysis 480
Pathologic Findings 480
Differential Diagnosis 480
Complications 481
Treatment 481
Specific Therapy 481
Supportive Care 481
Hereditary Elliptocytosis, Hereditary Pyropoikilocytosis, and Related Disorders 482
Clinical Syndromes 482
Pathophysiology 482
History and Physical 482
Laboratory Testing 483
Peripheral Blood Smear 483
Blood Count and Erythrocyte Indices 483
Osmotic Fragility 483
Molecular Studies 483
Markers of Hemolysis 483
Differential Diagnosis 483
Treatment and Outcome 483
Specific Therapy 483
Supportive Care 483
Complications and Outcome 483
Hereditary Stomatocytosis Syndromes 483
Xerocytosis 484
Hydrocytosis (Stomatocytosis) 484
Intermediate Syndromes 484
Acanthocytosis 484
Abetalipoproteinemia 484
McLeod Phenotype 484
Neuroacanthocytosis Syndromes 485
References 485
38 490
White Blood Cell and Immunodeficiency Disorders 490
Introduction 490
Severe Combined Immunodeficiency (Also See Chap. 2) 490
Antibody Deficiency 491
The Agammaglobulinemias 491
Hyper-IGM Syndrome (Elevated IGM, Decreased IGG, A, and E) (Also See Chap. 2) 493
Common Variable Immunodeficiency (Also See Chap. 2) 493
Cellular Deficiencies 494
Undue Susceptibility to Mycobacteria: IFNGAMMA/IL-12 AXIS 494
Autoimmunity 494
Lymphoproliferative Disorders 496
Phagocyte and Innate Defects 496
Chronic Granulomatous Disease 496
Leukocyte Adhesion Deficiency 496
Herpes Virus Encephalitis 497
References 497
39 501
Molecular Basis of Disorders of Hemostasis and Thrombosis 501
Introduction and Overview of Coagulation 501
Disorders of Soluble Clotting Factors 502
Fibrinogen (Factor I) Abnormalities 502
Prothrombin (Factor II) Deficiency 504
Factor V Deficiency 504
Factor VII Deficiency 504
Hemophilia A and Hemophilia B (Classic Hemophilia and Christmas Disease) 504
Factor X Deficiency 505
Factor XI Deficiency 505
Deficiencies of Factor XII, Prekallikrein, and High Molecular Weight Kininogen 505
Factor XIII Deficiency 505
Multiple Clotting Factor Deficiencies 506
Von Willebrand Disease 506
Acquired Clotting Factor Deficiencies 507
Disorders of Fibrinolysis 508
Disorders of Platelet Number or Function 508
Disorders of Platelet Production 508
The MYH9-Associated Disorders 508
Defects in Transcription Factors 509
Defects in Platelet Production 509
Disorders of Platelet Function 509
Defects in Platelet Adhesion 509
Defects in Platelet Aggregation 510
Disorders of Platelet Secretion: The Storage Pool Diseases 510
Defects in Alpha Granules 510
Defects in Dense Granules 510
The Scott Syndrome 511
Disorders of Platelet Destruction 511
Antibody-Mediated Platelet Destruction 511
Thrombotic Microangiopathies 512
Heparin-Induced Thrombocytopenia 512
Thrombophilia 512
The Protein C Pathway and Thrombosis 513
Antithrombin Deficiency 514
References 514
40 519
Sarcoidosis: Are There Sarcoidosis Genes? 519
Introduction 519
Morphology and Its Implications 519
Variants of Sarcoidosis 519
Löfgren’s Disease/Acute Sarcoidosis 519
Nodular Sarcoidosis 519
Necrotizing Sarcoid Granulomatosis 520
What Is the Meaning of Indistinguishable Differentials? 520
The Cells in Sarcoidosis 521
T Lymphocytes 521
Epithelioid Cells 521
Giant Cells (Foreign Body and Langerhans Type) 521
Mycobacteria and Other Trigger Mechanisms: Is Sarcoidosis an Infectious Disease? 522
Risk Factors 522
The Steps of an Immune Reaction and What Might Happen in Sarcoidosis 522
Antigen Uptake and Processing 523
Antigen Presentation, Costimulatory Molecules, and Gene Polymorphisms and Where They Come into Play 523
Human Leukocyte Antigen Class I Genes 524
Human Leukocyte Antigen Class II Genes 524
Effector Mechanisms, the Lymphocyte-Macrophage Network, and Gene Expression in Sarcoidosis 524
Disease Modifier Genes and Aspects of Organ Involvement in Sarcoidosis 526
References 527
41 530
Castleman’s Disease 530
Introduction 530
Clinical Classification 530
Unicentric Castleman’s Disease 530
Multicentric Castleman’s Disease 530
HIV Status and Castleman’s Disease 530
Epidemiology 531
Histopathological Classification of Castleman’s Disease 531
Relationship Between Histological Type and Clinical Classification 531
Pathogenesis of Castleman’s Disease 531
Diagnosis 532
Therapy 532
References 532
42 534
Molecular Pathology of Histiocytic Disorders 534
Introduction 534
Langerhans Cell Histiocytosis 534
Clinicopathologic Features 534
Immunohistochemistry of LCS in Normal Tissues and LCH 535
Host Genetic Factors in Langerhans Cell Histiocytosis 536
Epidemiologic Data 536
Increased Chromosomal Breakage in LCH Patients 536
The Role of Cytokines and Cytokine Gene Polymorphisms in LCH 536
HLA Haplotypes in LCH Patients 537
CD45 Splicing Defects 537
Clonality Studies in LCH 537
Conventional Cytogenetics and Ploidy Studies 537
HUMARA Studies 537
Comparative Genomic Hybridization (CGH) and Loss of Heterozigosity (LOH) Studies in LCH 537
Gene Expression Profiling in LCH 538
Alterations of Cell Cycle Proteins in LCH 538
Erdheim-Chester Disease 538
Clinicopathologic Features 538
Immunohistochemistry 539
Chemokine Network in ECD 539
Clonality Studies 539
Hemophagocytic Lymphohistiocytosis 539
Clinicopathology Features 539
Immunophenotypic and Immunologic Abnormalities 540
Host Genetic Factors in HLH 540
CD45 Splicing Abnormalities 541
Host Genetic Factors in SHLH 541
Cytokines in HLH 541
Juvenile Xanthogranuloma 541
Clinicopathologic Features 541
Immunohistochemistry 542
Proliferation and Apoptosis in JXG 542
Other Molecular Findings 542
Kikuchi-Fujimoto Disease (See Also Chaps. 43 and 44) 542
Clinicopathologic Features 542
Immunohistochemistry 542
HLA Subtypes in KFD 543
Infectious Agents in KFD 543
Lysosomal Storage Disorders 543
Clinicopathologic Features 543
References 546
43 550
Reactive Lymphadenopathies: Molecular Analysis 550
Overview 550
B Cell Processes 550
T Cell Processes 552
Specific Entities 553
Medication-Related Lymphoid Proliferations 554
References 554
44 557
Molecular Pathology of Infectious Lymphadenitides 557
Introduction 557
Bacterial Lymphadenitis 558
Bartonella spp. 558
Summary 561
T. whipplei (Whipple’s Disease) 561
Summary 562
C. trachomatis, Serovars L1–L3 (Lymphogranuloma Venereum, LGV) 562
Summary 563
T. pallidum (Syphilis) 563
Summary 564
Broad Range Detection of Bacteria 564
Mycobacterial Lymphadenitis 564
M. tuberculosis Complex 565
Mycobacteria Other Than Tuberculosis (MOTT) 566
General Mycobacterial Detection 567
Fungal Lymphadenitis 567
Introduction 567
Histoplasma capsulatum 567
Coccidioides 570
Cryptococcus neoformans 571
Panfungal Approaches to Molecular Mycology 571
Summary 572
Parasitic Lymphadenitis 572
Toxoplasma gondii 572
Leishmania spp. 573
Viral Lymphadenitis 574
Introduction 574
Herpesviruses 574
Other Viruses 575
Lymphadenitides of Suspected Infectious Origin 575
Kikuchi–Fujimoto Disease 575
Kimura Disease 575
Summary 576
References 576
45 584
Gene Therapy for Nonneoplastic Hematologic and Histiocytic Disorders 584
Introduction 584
Vectors for HSC Applications 584
Gammaretrovirus 584
Lentivirus 585
Alternate Retroviruses 585
Adenoviral Vectors 587
Adeno-Associated Virus Vectors 587
Nonviral Vectors 587
Early Studies 588
Clinical Trials 588
Recent Success 589
Hemophilias 589
Risks of Gene Therapy 590
Retrovirus Integration and Insertional Mutagenesis 590
Future Directions 591
Nonintegrating Vectors 591
Targeted Integration 591
References 592

Produkt-Details

• Erscheint lt. Verlag: 16.6.2010
• Reihe/Serie: Molecular Pathology Library
• Reihe/Serie: Molecular Pathology Library
• Mitarbeit: Herausgeber (Serie): Philip T. Cagle
• Zusatzinfo: XIX, 620 p. 122 illus., 93 illus. in color.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Allgemeines / Lexika
• Themenwelt: Medizin / Pharmazie ► Gesundheitsfachberufe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Studium ► 2. Studienabschnitt (Klinik) ► Pathologie
• Schlagworte: B-Cell • Bone marrow • Cancer • chromosome • Diagnostics • gene expression • gene therapy • Genetics • Genome • Hematolymphoid Diseases • Hematolymphoid Neoplasms • Hematopathology • Internal Medicine • Lymphoma • Molecular Biology • molecular genetics • Molecular Pathology • pathogenesis • Stem Cells • techniques
• ISBN-10: 1-4419-5698-0 / 1441956980
• ISBN-13: 978-1-4419-5698-9 / 9781441956989