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Written by a team of international experts, this book provides an authoritative overview and practical guide to the molecular biology and genetic basis of haematologic cancers including leukemia. Focusing on the importance of cytogenetics and related assays, both as diagnostic tools and as a basis for translational research, this is an invaluable guide for basic and clinical researchers with an interest in medical genetics and haemato-oncology. The Genetic Basis of Haematological Cancers reviews the etiology and significance of genetic and epigenetic defects that occur in malignancies of the…mehr
Written by a team of international experts, this book provides an authoritative overview and practical guide to the molecular biology and genetic basis of haematologic cancers including leukemia. Focusing on the importance of cytogenetics and related assays, both as diagnostic tools and as a basis for translational research, this is an invaluable guide for basic and clinical researchers with an interest in medical genetics and haemato-oncology. The Genetic Basis of Haematological Cancers reviews the etiology and significance of genetic and epigenetic defects that occur in malignancies of the haematopoietic system. Some of these chromosomal and molecular aberrations are well established and already embedded in clinical management, while many others have only recently come to light as a result of advances in genomic technology and functional investigation. The book includes seven chapters written by clinical and academic leaders in the field, organised according to haematological malignancy sub-type. Each chapter includes a background on disease pathology and the genetic abnormalities most commonly associated with the condition. Authors present in-depth discussions outlining the biological significance of these lesions in pathogenesis and progression, and their use in diagnosis and monitoring response to therapy. The current or potential role of specific abnormalities as novel therapeutic targets is also discussed. There is also a full colour section containing original FISH, microarrays and immunostaining images.
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Dr Sabrina Tosi graduated in Biological Sciences at the University of Milan (Italy) in 1989 and then attained her post-graduate degree in Human Cytogenetics at the University of Pavia (Italy) in 1992. Her interest in leukaemia dates back to 1989, when she started to work as a research scientist in the Department of Paediatric Haematology, Ospedale San Gerardo, Monza (Italy). In 1991-1992 Dr Tosi spent a year in the Oncogenetic Laboratory, Children's Hospital, University of Giessen (Germany) as a visiting research scientist. After another two years in Monza, Dr Tosi moved to the University of Oxford at the Weatherall Institute of Molecular Medicine, where she attained her DPhil in 1999 and spent altogether 12 years in leukaemia research. In 2005 she was appointed as Lecturer in Biosciences at Brunel University London, where she continues to work on the contribution of chromosomal abnormalities to leukaemia, with particular interest towards paediatric leukaemia. Dr Alistair Reid graduated in Genetics from the University of Newcastle upon Tyne in 1995, and trained as a diagnostic genetic scientist in the UK heath service. He obtained his PhD in Cambridge in 2003 based on the characterization of novel genetic prognosticators in myeloid leukemia. Since then he has held positions at several clinical academic haematology centres including Royal Free, London and University Children's Hospital, Zurich, and has also spent time as a consultant in the genetic diagnostics industry. In 2006 he was appointed Consultant Clinical Scientist in Molecular Pathology at Imperial College Healthcare Trust in London. He has an active laboratory-based translational research program focused on the genetics of myeloid leukemia and holds an honorary senior clinical lectureship for the development of novel methods of personalized genetic management in malignancy. Dr Reid has contributed to over 60 papers on malignancy genetics and was awarded fellowship of the Royal College of Pathologists in 2011.
Inhaltsangabe
List of contributors xi Preface xiii 1 The myelodysplastic syndromes 1 Cristina Mecucci, Valeria Di Battista and Valeria Nofrini Introduction 1 Predisposing conditions 2 Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) 2 Severe congenital neutropenia (SCN) 5 Poikiloderma with neutropenia 6 Familial MDS/AML 6 Shwachman-Diamond syndrome (SDS) 7 Dyskeratosis congenita (DKC) and telomere syndromes 8 Fanconi anaemia (FA) 11 Down syndrome 12 Cytogenetics 12 Loss of Y chromosome (-Y) and del(11q) 13 Del(20q) 15 idic(X)(q13) 15 Del(17)(p13)/i(17q) 15 Del(12p) 16 Trisomy 8 16 Rare trisomies: +6, +13, +14, +15, +16, +19, +21 16 Monosomy 7 and del(7q) 17 Rare monosomies 19 Unbalanced translocations involving 1q 19 t(17;18)(p10;q10) 20 Rare or sporadic balanced translocations 20 Complex karyotypes 22 Chromosome 5q deletions 23 Somatic mutations 31 Oncogenes and tumour suppressor genes 31 Mutations of genes involved in epigenetic modulation 39 Mutations of genes involved in the spliceosome machinery 45 Rare gene mutations in myelodysplastic syndromes 48 Epigenetics 49 DNA methylation 50 Histone modifications 52 RNA 53 Conclusion 54 References 54 2 Molecular genetics of the myeloproliferative neoplasms 80 Philip A. Beer Introduction 80 Overview of the different types of mutation found in MPN patients 80 Acquired mutations in cytokine signalling pathways 82 Acquired mutations in pathways controlling transcriptional regulation 84 Acquired mutations associated with transformation to advanced-phase disease 87 Inherited predisposition to clonal MPNs 87 Inherited non-clonal disorders that phenocopy distinct MPNs 87 Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) 88 Acquired mutations in cytokine signalling pathways (Table 2.3) 89 Acquired mutations in pathways controlling transcriptional regulation (Table 2.4) 95 Acquired mutations associated with progression to advanced and blastic-phase disease 101 Inherited predisposition to clonal MPNs 103 Inherited non-clonal disorders that phenocopy distinct MPNs 104 Principles and clinical utility of laboratory testing 107 Chronic eosinophilic leukaemia 109 Acquired mutations in cytokine signalling pathways 109 Acquired mutations in pathways controlling transcriptional regulation 113 Acquired mutations associated with progression to advanced and blastic-phase disease 113 Inherited predisposition to clonal MPNs 113 Inherited non-clonal disorders that phenocopy distinct MPNs 114 Principles and clinical utility of laboratory testing 114 Neoplastic mast cell disease 115 Acquired mutations in cytokine signalling pathways 116 Acquired mutations in pathways controlling transcriptional regulation 118 Acquired mutations associated with progression to advanced and blastic-phase disease 118 Inherited predisposition to clonal MPNs 119 Inherited non-clonal disorders that phenocopy distinct MPNs 119 Principles and clinical utility of laboratory testing 120 References 121 3 Acute myeloid leukaemia 133 Matthew L. Smith and Thomas McKerrell Introduction 133 AML classification 134 Cytogenetic aberrations 135 Fusion genes arising from structural rearrangements 135 Monosomies 148 Complex and monosomal karyotypes 148 Trisomies 148 Double minute chromosomes 151 Normal karyotype - is it really normal? 151 Altered gene expression 152 EVI1 152 BAALC 153 MN1 153 ERG 154 SET 154 BRE 154 WT1 154 miRNA genes 154 Diagnosis and classification of AML 155 Current risk stratification of AML patients: European LeukemiaNet (ELN) guidelines 156 Therapeutic regimens in AML 158 Management of younger adults aged 18-60 years 159 Older AML patients (aged >60 years) 159 Novel agents 160 Monitoring response to therapy (MRD) 160 The genomics of AML 161 Clonal evolution of AML 161 Established recurrent mutations in AML 163 Novel recurrent mutations in AML 173 Emerging concepts and future directions 179 Age-related clonal haematopoiesis (ARCH) 179 Application of genomic technologies to the diagnosis of AML 179 Conclusion 181 Mini-glossary 183 References 184 4 Molecular genetics of paediatric acute myeloid leukaemia 203 Marry van den Heuvel-Eibrink, Jasmijn D.E. de Rooij and Christian Michel Zwaan Clinical introduction 203 Epidemiology of AML 203 Diagnostic approach 204 Treatment and outcome 205 Relevant molecular and genetic aberrations in paediatric AML 206 Type I/II aberrations and their non-random associations 206 Relevance of type I/II aberrations for outcome and stratification of paediatric AML treatment 209 Epigenetic modifiers and hydroxymethylation pathway mutations 212 Further strategies 213 Further genomic approaches to unravelling the biology of paediatric AML 213 Molecularly targeted therapy 214 Conclusion 215 References 215 5 Acute lymphoblastic leukaemia 223 Anna Andersson, Anthony V. Moorman, Christine J. Harrison and Charles Mullighan Introduction 223 Chromosomal aberrations in BCP-ALL 224 High hyperdiploidy 227 t(12;21)(p13;q22)/ETV6-RUNX1 232 t(1;19)(q23;p13)/TCF3-PBX1 233 t(17;19)(q22;p13)/TCF3-HLF 234 Hypodiploidy 234 11q23/KMT2A (MLL) gene rearrangements 236 t(9;22)(q34;q11.1)/BCR-ABL1 237 Intrachromosomal amplification of chromosome 21 (iAMP21) 238 Complex karyotype 239 Submicroscopic genetic alterations in BCP-ALL 240 Alteration of transcription factors in BCP-ALL 241 CRLF2 rearrangements and Janus kinase mutations in ALL 242 BCR-ABL1-like or Ph-like ALL 243 ERG-altered ALL 245 Genetic rearrangements in T-lineage ALL 245 TAL1/LMO2 rearranged T-ALL 247 TLX1/TLX3 rearranged T-ALL 248 Early T-cell precursor ALL 249 Other T-ALL genetic subtypes: MLL rearranged and PICALM-MLLT10 250 Relapsed ALL 251 Future directions 252 References 252 6 The genetics of mature B-cell malignancies 265 Jonathan C. Strefford, Jude Fitzgibbon, Matthew J.J. Rose-Zerilli and Csaba Bödör Introduction 265 Chronic lymphocytic leukaemia 266 Immunoglobulin heavy-chain variable region gene mutational status 267 Chromosomal banding and interphase molecular cytogenetics 268 Copy number alterations 269 Deletions of 13q14 269 Trisomy 12 272 Deletions of 11q24 and mutations of ATM 273 Deletions of 17p13 and mutations of TP53 275 Other copy number alterations in CLL 276 Genome complexity and chromothripsis 277 Novel mutations in patients with CLL 279 NOTCH1 280 SF3B1 281 Other genes 282 Novel genetic mutations in clinical practice 282 Germinal centre lymphomas 284 Follicular lymphoma 286 Diffuse large B-cell lymphoma 293 Conclusions and future perspectives 296 Acknowledgements 299 References 299 7 The genetics of chronic myelogenous leukaemia 312 Philippa C. May, Jamshid S. Khorashad, Mary Alikian, Danilo Perrotti and Alistair G. Reid Introduction 312 Clinical features 313 The structure and physiological function of BCR and ABL1 316 The structure of the BCR-ABL1 fusion gene 317 Mechanisms of BCR-ABL1-induced oncogenesis 319 Potential mechanisms underlying the genesis of CML 320 CML blast crisis transformation 321 Tyrosine kinase inhibitor (TKI) therapy 325 The genetic basis of TKI resistance 326 Novel therapeutic approaches 330 Genetics in patient management 332 Cytogenetic and molecular cytogenetic monitoring 332 Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) 334 BCR-ABL1 mutation analysis 337 Conclusion 338 References 339 Index 359
List of contributors xi Preface xiii 1 The myelodysplastic syndromes 1 Cristina Mecucci, Valeria Di Battista and Valeria Nofrini Introduction 1 Predisposing conditions 2 Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) 2 Severe congenital neutropenia (SCN) 5 Poikiloderma with neutropenia 6 Familial MDS/AML 6 Shwachman-Diamond syndrome (SDS) 7 Dyskeratosis congenita (DKC) and telomere syndromes 8 Fanconi anaemia (FA) 11 Down syndrome 12 Cytogenetics 12 Loss of Y chromosome (-Y) and del(11q) 13 Del(20q) 15 idic(X)(q13) 15 Del(17)(p13)/i(17q) 15 Del(12p) 16 Trisomy 8 16 Rare trisomies: +6, +13, +14, +15, +16, +19, +21 16 Monosomy 7 and del(7q) 17 Rare monosomies 19 Unbalanced translocations involving 1q 19 t(17;18)(p10;q10) 20 Rare or sporadic balanced translocations 20 Complex karyotypes 22 Chromosome 5q deletions 23 Somatic mutations 31 Oncogenes and tumour suppressor genes 31 Mutations of genes involved in epigenetic modulation 39 Mutations of genes involved in the spliceosome machinery 45 Rare gene mutations in myelodysplastic syndromes 48 Epigenetics 49 DNA methylation 50 Histone modifications 52 RNA 53 Conclusion 54 References 54 2 Molecular genetics of the myeloproliferative neoplasms 80 Philip A. Beer Introduction 80 Overview of the different types of mutation found in MPN patients 80 Acquired mutations in cytokine signalling pathways 82 Acquired mutations in pathways controlling transcriptional regulation 84 Acquired mutations associated with transformation to advanced-phase disease 87 Inherited predisposition to clonal MPNs 87 Inherited non-clonal disorders that phenocopy distinct MPNs 87 Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) 88 Acquired mutations in cytokine signalling pathways (Table 2.3) 89 Acquired mutations in pathways controlling transcriptional regulation (Table 2.4) 95 Acquired mutations associated with progression to advanced and blastic-phase disease 101 Inherited predisposition to clonal MPNs 103 Inherited non-clonal disorders that phenocopy distinct MPNs 104 Principles and clinical utility of laboratory testing 107 Chronic eosinophilic leukaemia 109 Acquired mutations in cytokine signalling pathways 109 Acquired mutations in pathways controlling transcriptional regulation 113 Acquired mutations associated with progression to advanced and blastic-phase disease 113 Inherited predisposition to clonal MPNs 113 Inherited non-clonal disorders that phenocopy distinct MPNs 114 Principles and clinical utility of laboratory testing 114 Neoplastic mast cell disease 115 Acquired mutations in cytokine signalling pathways 116 Acquired mutations in pathways controlling transcriptional regulation 118 Acquired mutations associated with progression to advanced and blastic-phase disease 118 Inherited predisposition to clonal MPNs 119 Inherited non-clonal disorders that phenocopy distinct MPNs 119 Principles and clinical utility of laboratory testing 120 References 121 3 Acute myeloid leukaemia 133 Matthew L. Smith and Thomas McKerrell Introduction 133 AML classification 134 Cytogenetic aberrations 135 Fusion genes arising from structural rearrangements 135 Monosomies 148 Complex and monosomal karyotypes 148 Trisomies 148 Double minute chromosomes 151 Normal karyotype - is it really normal? 151 Altered gene expression 152 EVI1 152 BAALC 153 MN1 153 ERG 154 SET 154 BRE 154 WT1 154 miRNA genes 154 Diagnosis and classification of AML 155 Current risk stratification of AML patients: European LeukemiaNet (ELN) guidelines 156 Therapeutic regimens in AML 158 Management of younger adults aged 18-60 years 159 Older AML patients (aged >60 years) 159 Novel agents 160 Monitoring response to therapy (MRD) 160 The genomics of AML 161 Clonal evolution of AML 161 Established recurrent mutations in AML 163 Novel recurrent mutations in AML 173 Emerging concepts and future directions 179 Age-related clonal haematopoiesis (ARCH) 179 Application of genomic technologies to the diagnosis of AML 179 Conclusion 181 Mini-glossary 183 References 184 4 Molecular genetics of paediatric acute myeloid leukaemia 203 Marry van den Heuvel-Eibrink, Jasmijn D.E. de Rooij and Christian Michel Zwaan Clinical introduction 203 Epidemiology of AML 203 Diagnostic approach 204 Treatment and outcome 205 Relevant molecular and genetic aberrations in paediatric AML 206 Type I/II aberrations and their non-random associations 206 Relevance of type I/II aberrations for outcome and stratification of paediatric AML treatment 209 Epigenetic modifiers and hydroxymethylation pathway mutations 212 Further strategies 213 Further genomic approaches to unravelling the biology of paediatric AML 213 Molecularly targeted therapy 214 Conclusion 215 References 215 5 Acute lymphoblastic leukaemia 223 Anna Andersson, Anthony V. Moorman, Christine J. Harrison and Charles Mullighan Introduction 223 Chromosomal aberrations in BCP-ALL 224 High hyperdiploidy 227 t(12;21)(p13;q22)/ETV6-RUNX1 232 t(1;19)(q23;p13)/TCF3-PBX1 233 t(17;19)(q22;p13)/TCF3-HLF 234 Hypodiploidy 234 11q23/KMT2A (MLL) gene rearrangements 236 t(9;22)(q34;q11.1)/BCR-ABL1 237 Intrachromosomal amplification of chromosome 21 (iAMP21) 238 Complex karyotype 239 Submicroscopic genetic alterations in BCP-ALL 240 Alteration of transcription factors in BCP-ALL 241 CRLF2 rearrangements and Janus kinase mutations in ALL 242 BCR-ABL1-like or Ph-like ALL 243 ERG-altered ALL 245 Genetic rearrangements in T-lineage ALL 245 TAL1/LMO2 rearranged T-ALL 247 TLX1/TLX3 rearranged T-ALL 248 Early T-cell precursor ALL 249 Other T-ALL genetic subtypes: MLL rearranged and PICALM-MLLT10 250 Relapsed ALL 251 Future directions 252 References 252 6 The genetics of mature B-cell malignancies 265 Jonathan C. Strefford, Jude Fitzgibbon, Matthew J.J. Rose-Zerilli and Csaba Bödör Introduction 265 Chronic lymphocytic leukaemia 266 Immunoglobulin heavy-chain variable region gene mutational status 267 Chromosomal banding and interphase molecular cytogenetics 268 Copy number alterations 269 Deletions of 13q14 269 Trisomy 12 272 Deletions of 11q24 and mutations of ATM 273 Deletions of 17p13 and mutations of TP53 275 Other copy number alterations in CLL 276 Genome complexity and chromothripsis 277 Novel mutations in patients with CLL 279 NOTCH1 280 SF3B1 281 Other genes 282 Novel genetic mutations in clinical practice 282 Germinal centre lymphomas 284 Follicular lymphoma 286 Diffuse large B-cell lymphoma 293 Conclusions and future perspectives 296 Acknowledgements 299 References 299 7 The genetics of chronic myelogenous leukaemia 312 Philippa C. May, Jamshid S. Khorashad, Mary Alikian, Danilo Perrotti and Alistair G. Reid Introduction 312 Clinical features 313 The structure and physiological function of BCR and ABL1 316 The structure of the BCR-ABL1 fusion gene 317 Mechanisms of BCR-ABL1-induced oncogenesis 319 Potential mechanisms underlying the genesis of CML 320 CML blast crisis transformation 321 Tyrosine kinase inhibitor (TKI) therapy 325 The genetic basis of TKI resistance 326 Novel therapeutic approaches 330 Genetics in patient management 332 Cytogenetic and molecular cytogenetic monitoring 332 Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) 334 BCR-ABL1 mutation analysis 337 Conclusion 338 References 339 Index 359
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