The haematological malignancies are a complex group of neoplastic diseases, linked by their origin in bone marrow-derived cells. Since the discovery of the Philadelphia chromosome, in the 1960s, as the pathognomonic marker of chronic myeloid leukaemia, the field of haematological malignancy has provided several important paradigms for the direct contribution of causal genetic lesions to the initiation of human cancer.
The subsequent leap in our understanding of leukaemia and lym-phoma pathogenesis via a variety of molecular and cytogenetic abnormalities that disrupt normal cellular processes has challenged traditional approaches to disease classification and transformed both the diagnosis and management of patients. The characterization of tumour cells by genetic methods is now regarded as being as important as the traditional morphological approach to diagnosis. This trend is being accelerated by the introduction of monoclonal antibody therapy and by novel drugs designed to target specifically the molecular abnormalities responsible for the development of the tumour. Somatic genetic changes therefore increasingly define not just the diseases themselves, but the way in which an individual patient should best be treated and monitored.
With the following chapters, compiled by leading researchers in the field, we aim to provide a summary of current knowledge on the contribution of genetic and epigenetic lesions to the biology and management of haematological malignancies. A unifying factor of these biologically diverse diseases is the recent explosion of information on hitherto unrecognized molecular lesions arising from the application of novel next-generation sequencing technologies. In most diseases, these newly identified aberrations are already contributing to improved stratification and, in some cases, showing early promise as therapeutic targets. It is hoped that further functional analysis of recurrent lesions will permit the development of additional therapies targeted against critical oncogenic drivers. Although the majority of recurrent changes appear to have been identified, there remains scope for further refinement of this knowledge with studies of larger cohorts, the increasing use of whole genome sequencing, greater incorporation of rearrangement-based bioinformatic analysis and enhanced integration with epigenomic data. These areas, together with the investigation of the importance of sequential acquisition of mutations in the initiation of a malignant phenotype and the interaction of these lesions with the bone marrow microenvironment, are likely to keep researchers occupied for the foreseeable future. Nevertheless, as the following chapters beautifully illustrate, a comprehensive picture is emerging of the key genetic drivers of haematological malignancy, and these provide a rational basis for future research towards a complete understanding of, and effective treatment for, this complex group of diseases.

List of contributors xi

Preface xiii

1 The myelodysplastic syndromes 1

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(llq) 13

      Del(20q) 15

      idic(X)(ql3) 15

      Del(17)(pl3)/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)(pl0;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

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

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

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 II1I 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

Introduction 223

Chromosomal aberrations in BCP-ALL 224

      High hyperdiploidy 227

      t(12;21) (p 13;q22)/ETV6-R UNXI 232

      t(l;19)(q23;p13)/TCF3-PBXl 233

      t(17;19)(q22;pl3)/TCF3-HLF 234

      Hypodiploidy 234

      Ilq23/KMT2A (MLL) gene rearrangements 236

      t(9;22) (q34;ql 1.1)/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/LM02 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

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 13ql4 269

      Trisomy 12 272

      Deletions of 11 q24 and mutations of ATM 273

      Deletions of 17pl3 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

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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