PhD Anthony J. Bench (Postdoctoral Research Associate), MD, PhD Elisabeth P. Nacheva (Head of Molecular Cytogenetics Laboratory), Kim M. Champion (Research Assistant), PhD, FRCP, FRCPath Anthony R. Green (Wellcome Senior Fellow and Honorary Consultant Haematologist)
{"title":"7 Molecular genetics and cytogenetics of myeloproliferative disorders","authors":"PhD Anthony J. Bench (Postdoctoral Research Associate), MD, PhD Elisabeth P. Nacheva (Head of Molecular Cytogenetics Laboratory), Kim M. Champion (Research Assistant), PhD, FRCP, FRCPath Anthony R. Green (Wellcome Senior Fellow and Honorary Consultant Haematologist)","doi":"10.1016/S0950-3536(98)80041-3","DOIUrl":"10.1016/S0950-3536(98)80041-3","url":null,"abstract":"<div><p>The myeloproliferative disorders are believed to represent clonal malignancies resulting from transformation of a pluripotent stem cell. X-inactivation patterns of peripheral blood cells have been proposed as a useful diagnostic tool but this method is limited by the finding of a clonal X-inactivation pattern in a significant proportion of normal elderly women. There is no pathognomonic chromosomal abnormality associated with the myeloproliferative disorders. However, consistent acquired cytogenetic changes include del(20q), del(13q), trisomy 8 and 9 and duplication of segments of 1q, all of which have been observed at diagnosis or before cytoreductive therapy and therefore represent early lesions which contribute to the pathogenesis of these disorders. Although, the acquired molecular defects underlying most myeloproliferative disorders have not yet been elucidated, translocations associated with the rare 8p11 syndrome have permitted identification of a novel fusion protein. The role of a number of candidate genes in the other myeloproliferative disorders has also been studied, but no mutations have been identified so far. It is likely that a number of genes will be involved, given the varied phenotypes of the diseases. Identification of causal genes will be of considerable interest to both clinicians, who currently lack a specific and sensitive diagnostic test, and scientists interested in fundamental issues of stem cell behaviour.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"11 4","pages":"Pages 819-848"},"PeriodicalIF":0.0,"publicationDate":"1998-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(98)80041-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21496315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MD Jean Briere (Professor), PhD Nahed El-Kassar (Assistant)
{"title":"5 Clonality markers in polycythaemia and primary thrombocythaemia","authors":"MD Jean Briere (Professor), PhD Nahed El-Kassar (Assistant)","doi":"10.1016/S0950-3536(98)80039-5","DOIUrl":"10.1016/S0950-3536(98)80039-5","url":null,"abstract":"<div><p>Our current understanding of the pathogenesis of the myeloproliferative disorders is based on the assumption that they represent a clonal disorder resulting from transformation of a haematopoietic stem cell. Clonality assays exploit the fact that female cells have only one active X-chromosome. Methods for determining X chromosome inactivation have been devised at the protein (G6PD isoenzymes), DNA (HUMARA; phosphoglycerate kinase (PGK); hypoxanthine-phosphoribosyl transferase (HRPT)) and RNA (G6PD; P55; IDS) levels. In this type of RNA assay the product of the active X chromosome is quantified by studying polymorphisms present in mRNA. The presence of skewed lyonization in normal females is a potential limitation to the method, although the use of T cells as a control makes it possible to distinguish clonal haematopoiesis from skewed lyonization. However, the phenomenon of acquired skewing in normal elderly women means that X-inactivation patterns in elderly patients must be interpreted with caution. Clonality studies have been conducted in polycythaemia vera (PV) and essential thrombocythaemia (ET) patients. They usually demonstrate a clonal X-inactivation pattern in granulocytes and/or platelets but a polyclonal pattern in T cells. However, in both ET and PV a significant minority of patients exhibit polyclonal haematopoiesis with polyclonal patterns in granulocytes/platelets. Female patients with polyclonal haematopoiesis differ from those with clonal haematopoiesis in terms of age and platelet count and possibly in their requirements for treatment. This new technology for the investigation of the MPD seems promising for understanding certain clinical aspects of these diseases and may be introduced for evaluation of new modalities of treatment.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"11 4","pages":"Pages 787-801"},"PeriodicalIF":0.0,"publicationDate":"1998-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(98)80039-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21496310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhD, FRCP, FRCPath Finbarr E. Cotter (Reader in Haematology and Oncology)
{"title":"10 Childhood myeloproliferative disorders","authors":"PhD, FRCP, FRCPath Finbarr E. Cotter (Reader in Haematology and Oncology)","doi":"10.1016/S0950-3536(98)80044-9","DOIUrl":"10.1016/S0950-3536(98)80044-9","url":null,"abstract":"<div><p>Disorders classified as paediatric myeloproliferative disorders (MPD), such as juvenile chronic myeloid leukaemia (JCML), and as paediatric myelodysplastic syndrome (MDS), are essentially diseases characterized by abnormal myeloproliferation and they share similar genetic events on chromosome 7. As such, the abnormalities of increased myeloproliferation in childhood (AIMC) should be considered under the same heading. Constitutional and other genetic factors play an essential role in children and include the NF1 gene, whereas toxic exposure is of greater importance in adults. The most common cytogenetic alteration is that of monosomy or deletion of the long arm of chromosome 7. Critical regions have been identified and mapped by fluorescence in situ hybridization (FISH). It appears that the similar critical regions on chromosome 7 are involved, and suggests that these regions may contain genes important in the pathogenesis of AIMC.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"11 4","pages":"Pages 875-898"},"PeriodicalIF":0.0,"publicationDate":"1998-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(98)80044-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21495922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MD Harriet S. Gilbert (Clinical Professor of Medicine)
{"title":"8 Familial myeloproliferative disease","authors":"MD Harriet S. Gilbert (Clinical Professor of Medicine)","doi":"10.1016/S0950-3536(98)80042-5","DOIUrl":"10.1016/S0950-3536(98)80042-5","url":null,"abstract":"<div><p>The occurrence of one or more myeloproliferative disease (MPD) syndromes in 42 families is described. MPD appeared in a single generation in 10 families, two generations in 30 families and three generations in two families. In contrast to sparse case reports of familial polycythaemia vera, familial essential thrombocythaemia, or familial agnogenic myeloid metaplasia, in which all the involved members presented with the same MPD, 21 of the 42 families in the present series had members who presented with different MPD variants. The occurrence of multiple disease phenotypes in ‘MPD families’ is entirely consistent with the accepted theory of MPD as a disease arising from clonal expansion of a pluripotential haematopoietic precursor cell (PHPC) that retains its pluripotentiality and produces an array of inter-related syndromes, each named for the predominant haematic cell type involved in the proliferation. Changes in disease phenotype during the course of MPD and ‘hybrid’ phenotypes at the time of diagnosis are common. This report challenges the previously accepted belief that PV and other MPD variants are sporadic and randomly-occurring, and that familial occurrence of MPD is rare. The ability to identify ‘MPD families’ by surveying a large population of patients with MPD through the Internet, as was done in this study, and heightened awareness of familial occurrence and its phenotypic heterogeneity, should facilitate further characterization of the mode of inheritance in familial MPD and the nature of the gene mutations responsible for the dysregulation of haematopoiesis.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"11 4","pages":"Pages 849-858"},"PeriodicalIF":0.0,"publicationDate":"1998-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(98)80042-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21496314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhD Robert Kralovics (Research Instructor), MD Josef T. Prchal (Professor of Medicine and Biochemistry)
{"title":"6 Haematopoietic progenitors and signal transduction in polycythaemia vera and primary thrombocythaemia","authors":"PhD Robert Kralovics (Research Instructor), MD Josef T. Prchal (Professor of Medicine and Biochemistry)","doi":"10.1016/S0950-3536(98)80040-1","DOIUrl":"10.1016/S0950-3536(98)80040-1","url":null,"abstract":"<div><p>While significant progress has been made in understanding the cellular defect and molecular basis of polycythaemia vera (PV), elucidation of the primary mutation leading to PV remains elusive. While clinically useful, the PV diagnostic criteria put forward by the Polycythemia Vera Study Group are not based on the pathophysiology of this disorder and in some instances may lead to false diagnosis or may not be sufficient to diagnose an early PV. In diagnostically unclear situations, clinical and laboratory findings must take into account the acquired nature of PV, its clonality, and the presence of endogenous erythroid colony formation in serum-containing media. It is likely that other simpler assays may be developed based on the rapidly emerging knowledge of the cellular pathology of PV. Several intriguing observations of abnormalities pertaining to the erythroid signal transduction have been recently reported; these remain to be validated in other laboratories and to be proven specific for PV. The clinical concept of primary thrombocythaemia (PT) lags behind what we know about PV. While the diagnosis of PT is still based on the exclusion of other known causes of thrombocytosis, new knowledge is emerging. Recent clonality studies of a large number of PT females show that the majority are clonal. It is our belief that thrombocythaemic subjects who are not found to be clonal are those with secondary thrombocytosis. Multiple in vitro-based assays of megakaryocytic and erythroid progenitors have been developed and conflicting data published. It is likely that standardized assays of megakaryocytic progenitors will soon become available and a reproducible PT specific defect will be found. Such a specific test would be of immense diagnostic value in this most elusive of all myeloproliferative disorders.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"11 4","pages":"Pages 803-818"},"PeriodicalIF":0.0,"publicationDate":"1998-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(98)80040-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21496311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MD Martin Griesshammer (Head, Laboratory of Research on Haemostasis), MD Lothar Bergmann (Professor of Haematology), MD, FRCPath Tom Pearson (Professor of Haematology)
{"title":"9 Fertility, pregnancy and the management of myeloproliferative disorders","authors":"MD Martin Griesshammer (Head, Laboratory of Research on Haemostasis), MD Lothar Bergmann (Professor of Haematology), MD, FRCPath Tom Pearson (Professor of Haematology)","doi":"10.1016/S0950-3536(98)80043-7","DOIUrl":"10.1016/S0950-3536(98)80043-7","url":null,"abstract":"<div><p>The management of pregnant patients with chronic myeloproliferative disorders (MPD) is a difficult problem. Patients with essential thrombocythaemia (ET), and, less frequently, those with chronic myeloid leukaemia (CML) or polycythaemia vera (PV), present at a childbearing age. Pregnancy itself does not appear to affect adversely the natural course and prognosis of the MPD. However, fertility might be reduced, and an adverse outcome of pregnancy due to thrombotic or bleeding complications is a matter of concern. In ET, first-trimester abortion is the most frequent complication but increased perinatal mortality and premature delivery are also observed. Placental infarction due to thrombosis seems to be the most consistent event. Maternal thrombotic or haemorrhagic complications are rare but are more common than seen in normal pregnancy. The outcome of pregnancy seems to be positively influenced by aspirin, at least in some cases. The value of cytoreduction and/or heparin prophylaxis has not been established but may have a role in selected cases. In CML, the potential adverse effects of hyperleukocytosis, and sometimes thrombocytosis, generally make myelosuppressive treatment essential. In PV, the number of reported pregnancies is low. Maintaining the PCV below 0.45 is of the utmost importance relating to the outcome of pregnancy. Although cytoreductive drugs should generally be avoided, if possible, until at least after the first trimester of pregnancy, interferon-α seems to be the drug of choice when myelosuppression is indicated.</p><p>In summary, the available information about pregnancy occurring during the course of an MPD indicates that successful management of pregnancy is possible. However, optimal management of these patients is poorly defined and agreed protocols are not available. In view of these problems, it is timely to consider the establishment of a national or European registry to monitor prospectively the management offered to pregnant women found to have an MPD.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"11 4","pages":"Pages 859-874"},"PeriodicalIF":0.0,"publicationDate":"1998-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(98)80043-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21496316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dr. Med. A. Georgii, Dr. Med. G. Buesche (em. Professor of Pathology), Dr. Med. A. Kreft
{"title":"2 The histopathology of chronic myeloproliferative diseases","authors":"Dr. Med. A. Georgii, Dr. Med. G. Buesche (em. Professor of Pathology), Dr. Med. A. Kreft","doi":"10.1016/S0950-3536(98)80036-X","DOIUrl":"10.1016/S0950-3536(98)80036-X","url":null,"abstract":"<div><p>This chapter discusses the histopathology of five groups of chronic myeloproliferative diseases: chronic myeloid leukaemia, polycythaemia vera, essential thrombocythaemia, chronic idiopathic myelofibrosis and unclassifiable myeloproliferation. Histological staging of the four haematologically defined diseases is performed by grading the three most prominent variables: megakaryocytes, fibres and blasts. Histological outcome is correlated to the staging of diagnostic bone marrow biopsies; megakaryocytic involvement is correlated with the risk of myelofibrosis. An excess of blasts is related to the risk of leukaemic transformation. The progression of myelofibrosis depends on the grade of fibre increase at diagnosis. These three statements are highly significant and valid for all types of chronic myeloproliferative disorders. The results of cytogenetics are discussed in relation to the histological classification for these patient groups. Changes in bone marrow histology following myelosuppressive therapy is presented. Prospective studies under standardized protocol therapy are recommended, so that the long-term effects of therapy can be assessed.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"11 4","pages":"Pages 721-749"},"PeriodicalIF":0.0,"publicationDate":"1998-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(98)80036-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21495842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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