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.
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.
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.
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.
Preface
Chapter 1: Introduction
Chapter 2: Molecular genetics of the myeloproliferative neoplasms
Philip A Beer
Chapter 3: Acute Myeloid Leukaemia
Dr Matthew L Smith and Dr Thomas McKerrell
Chapter 4: Molecular genetics of Pediatric Acute Myeloid Leukemia (AML)
MM van den Heuvel-Eibrink, JDE de Rooij, and CM Zwaan
Chapter 5: Acute Lymphoblastic Leukemia
Anna Andersson, Anthony V. Moorman, Christine J. Harrison and Charles Mullighan
Chapter 6: The Genetics of mature B-cell malignancies
Jonathan C Strefford, Jude Fitzgibbon, Matthew JJ Rose-Zerilli and Csaba Bödör
Chapter 7: The Genetics of Chronic Myelogenous Leukaemia
Philippa C May, Jamshid S Khorashad, Mary Alikian, Danilo Perrotti and Alistair G Reid
Index
Chapter 1
The myelodysplastic syndromes
Cristina Mecucci, Valeria Di Battista and Valeria Nofrini
Introduction
Myelodysplastic syndromes (MDS) define neoplastic disorders with bone marrow dysplasia and insufficiency leading to one or more cytopenia in the peripheral blood. Bone marrow differentiation, although abnormal, is maintained. Despite the reduced amount of circulating blood cells, bone marrow cellularity is increased in the majority of cases. Less frequently, the bone marrow is hypoplastic, particularly in children and young adults with a predisposing genetic condition. The large majority of MDS cases affect individuals over the age of 60 years. Blast count, by definition, is less than 20%, although a minority of cases (10–20%) eventually transform to acute myeloid leukaemia (AML), defined by a blast count of 20% or more.
As bone marrow dysplasia may be induced from a variety of non-neoplastic conditions, including vitamin deficiencies, viral infections, smoking or medication, the identification of clonal genetic aberrations detected by chromosome banding or higher throughput genomic technologies plays a key role in achieving the correct diagnosis. Conventional cytogenetic analysis is able to detect abnormalities in around 40–50% of cases of de novo MDS, increasing to around 70–80% when integrated with whole-genome analysis detecting copy-number variations, uniparental disomy and acquired mutations.1–3 Cytogenetic abnormalities involving partial or complete chromosome loss are more frequent than reciprocal translocations. This is in contrast to AML, which is partly subcategorized according to the presence of typical reciprocal chromosome translocations, such as t(8;21), t(15;17) and inv(16). Importantly, the latter are consistent with a diagnosis of AML, even in the presence of morphological evidence of less than 20% bone marrow blasts.4
The incidence of chromosome aberrations is much higher in MDS arising after chemo- or radiotherapy, including bone marrow transplantation procedures, for a prior neoplastic or non-neoplastic disease. A complex abnormal karyotype is found in more than 80% of treatment-induced MDS.
The critical role of clonal cytogenetic defects at diagnosis is underlined by the hierarchical clonal evolution and acquisition of additional chromosomal defects that often accompany disease progression. In addition to chromosomal rearrangements, newly acquired gene mutations may also mark clonal evolution and disease progression.5–7 These changes may contribute to the development of a higher risk MDS or AML by conveying growth advantage, decreased apoptosis or avoidance of immune control.8 The identification of driver gene mutations might also help define distinctive entities within myelodysplastic syndromes, improving classification and clinical management.9 This chapter summarizes the current understanding of the genetic and epigenetic landscape of MDS and known predisposing conditions.
Predisposing conditions
Several inherited or congenital conditions have been associated with a predisposition to develop myelodysplasia. These conditions are characterized by the presence of inherited genetic defects and the development of MDS is often linked to additional genetic mistakes that are acquired and confined to the myeloid lineage. Table 1.1 summarizes the conditions described in this section and includes a list of constitutional genetic defects associated with the disorders.
Table 1.1 Inherited or congenital conditions predisposing to MDS and leukaemia
| Disease | Inheritance | Gene | Locus | Other features | Incidence of MDS/AML (%) |
| Severe congenital neutropenia | AD | ELANE | 19q13 | None | 10 |
| AD | GFI1 | 1p22 | Monocytosis Lymphopenia |
| AR | GSPC3 | 17q24 | Cardiac and urogenital malformations |
| AR | HAX1 | 1q21 | Neuropsychological defects |
| XL | WAS | Xp11 | Monocytopenia Low NK cells |
| Shwachman–Diamond syndrome | AR | SBDS | 7q11 | Exocrine pancreatic insufficiency, bone marrow failure, skeletal abnormalities | 10 |
| Poikiloderma with neutropenia | AR | C16orf57 | 16q21 | Poikiloderma, pachyonychia, chronic neutropenia |
| Dyskeratosis congenita | XL | DKC1 | Xq28 | Mucocutaneous abnormalities, aplastic anaemia | 3–5 |
| Fanconi anaemia | AR | FANC/BRCA | Xp22 | Multiple congenital abnormalities | 50 |
| XL | FANCB |
| Bloom syndrome | AR | BLM | 15q26 | Short stature, photosensitivity reactions | 25 |
| Familial platelet disorder with propensity to myeloid malignancy | AD | RUNX1 | 21q22 | Dysmorphic features, intellectual disability (in cases with RUNX1 deletions) | 20–60 |
| Familial MDS/AML with GATA2 mutations | ? | GATA2 | 3q21 | Monocytopenia, B, NK and dendritic cell lymphopenia |
| Down syndrome | N/A | HMGN1 | 21q22.2 | Delayed development, learning disabilities, heart defects, vision problems, hearing loss, hypotonia | 10–20-fold higher than general population |
| SCN | AD | ELANE | 19q13 | None | 10 |
| AD | GFI1 | 1p22 | Monocytosis Lymphopenia |
| AR | GSPC3 | 1p34 | Cardiac and urogenital malformations |
| AR | HAX1 | 1q21 | Neuropsychological defects |
| XL | WAS | Xp11 | Monocytopenia Low NK cells |
| SDS | AR | SBDS | 7q11 | Exocrine pancreatic insufficiency and skeletal abnormalities | 10 |
| PN | AR | C16orf57 | 16q21 | Poikiloderma, pachyonychia, chronic neutropenia |
| DC | XL | DKC1 | Xq28 | Mucocutaneous abnormalities, aplastic anaemia | 3–5 |
| FA | AR | FANC/BRCA | 50 |
| XL |
| BS | AR | BLM | 15q26 | Short stature, photosensitivity reactions | 25 |
| FPD/AML | AD | RUNX1 | 21q22 | Dysmorphic features and intellectual disability (in cases with deletions) | 20–60 |
| Familial MDS/AML with GATA2 mutations | ? | GATA2 |
AD, autosomal dominant; AR; autosomal recessive; XL, X-linked; N/A, not applicable.
Familial platelet disorder with propensity to myeloid malignancy (FPD/AML)
Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant disease characterized by mild to moderate bleeding tendency and modest thrombocytopenia with normal platelet size and morphology. Predisposition to develop myelodysplasia and acute leukaemia is another feature of this platelet disorder, with a leukaemic rate of approximately 35%.10 The majority of patients exhibit impaired platelet aggregation with collagen and epinephrine, similarly to abnormalities caused by aspirin. FDP/AML is associated with alterations of RUNX1/21q22.12, a gene encoding for a subunit of the core binding factor (CBF) transcription complex. Monoallelic mutations in RUNX1 include deletions and missense, nonsense and frameshift mutations.11 Two functional consequences of these mutations include haploinsufficiency and a dominant negative effect.12 Large deletions of RUNX1 have also been described, and in these cases patients showed additional features such as short stature, malformations, dysmorphic features and intellectual disability.13 Individuals with missense mutations have a higher risk of haematological malignancies than those carrying mutations causing haploinsufficiency.14 However, the genetics of FPD/AML may be even more complicated; Minelli et al.15 reported a single family with a clinical history consistent with FDP/AML in which no mutations was detected in RUNX1 and in which linkage to chromosome 21 was excluded, implying that other genetic lesions outside this region may also cause an FDP/AML-like phenotype.
Severe...
| Erscheint lt. Verlag | 2.3.2016 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizinische Fachgebiete ► Innere Medizin ► Hämatologie |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie | |
| Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik | |
| Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
| Technik | |
| Schlagworte | Biowissenschaften • blood cancers • cytogenetics • Genetics • Genetik • genomics • Hämatologie • Haemato-oncology • Hämatologie • Leukaemia • Life Sciences • medical genetics • Medical oncology • Medical Science • Medizin • Medizinische Genetik • medizinische Onkologie • Molecular Pathology • Myelodysplastic Syndrome (MDS) • Myeloproliferative Neoplasm (MPN) • Non-Hodgkin Lymphoma (NHL) • Onkologie |
| ISBN-13 | 9781118528051 / 9781118528051 |
| Informationen gemäß Produktsicherheitsverordnung (GPSR) | |
| Haben Sie eine Frage zum Produkt? |
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