Preface: Thalassemia Bernard G. Forget

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1 Thalassemia Preface: Thalassemia Bernard G. Forget xiii Thalassemia: An Overview of 50 Years of Clinical Research 1005 Vijay G. Sankaran and David G. Nathan The thalassemias are attributable to the defective production of the a- and b-globin polypeptides of hemoglobin. Significant discoveries have illuminated the pathophysiology and enhanced the prevention and treatment of the thalassemias, and this article reviews many of the advances that have occurred in the past 50 years. However, the application of new approaches to the treatment of these disorders has been slow, particularly in the developing world where the diseases are common, but there is definite progress. This article emphasizes how the increasing knowledge of cellular and molecular biology are facilitating the development of more effective therapies for these patients. The Population Genetics and Dynamics of the Thalassemias 1021 D.J. Weatherall, T.N. Williams, S.J. Allen, and A. O Donnell The inherited disorders of hemoglobin, including the thalassemias, are by far the commonest monogenic diseases. Although several factors are responsible for their very high frequency, the major mechanism seems to be natural selection mediated by heterozygote protection against severe forms of malaria. Recent work has highlighted the complexity of the interplay among the different hemoglobin variants themselves and among different levels of malaria resistance, and is helping to explain the extraordinary heterogeneity in the distribution of the hemoglobin disorders even within short geographical distances. Some progress has also been made toward understanding the cellular and immune mechanisms that may underlie heterozygote protection against malaria in these conditions. In addition to providing valuable information about human evolutionary biology, work in this field has an increasingly important influence on the development of programs for the better management of the hemoglobin disorders, particularly in the poorer countries of the tropical world. The Molecular Basis of a-thalassemia: A Model for Understanding Human Molecular Genetics 1033 Douglas R. Higgs and Richard J. Gibbons Down-regulation of a-globin synthesis causes a-thalassemia with underproduction of fetal (HbF, a 2 g 2 ) and adult (HbA, a 2 b 2 ) hemoglobin. This article focuses on the human a-globin cluster, which has been characterized in great depth over the past 30 years. In particular the authors describe how the a genes are normally switched on during erythropoiesis and switched off as hematopoietic stem cells commit to nonerythroid lineages. In addition, the principles by which a-globin expression may be perturbed by natural mutations that cause a-thalassemia are reviewed.

2 viii HbE/b-Thalassemia: Basis of Marked Clinical Diversity 1055 Nancy F. Olivieri, Zahra Pakbaz, and Elliott Vichinsky Hemoglobin E thalassemia accounts for about one-half of all cases of severe beta thalassemia. There is marked variability in its clinical severity ranging from an asymptomatic to a transfusion-dependent phenotype. The phenotypic variability and inadequate longitudinal data present challenges in determining the optimal management of patients. This article summarizes findings on the natural history of Hemoglobin E thalassemia and some factors responsible for its clinical heterogeneity. Major genetic factors include the type of beta thalassemia mutation, the co-inheritance of alpha thalassemia, and polymorphisms associated with increased synthesis of fetal hemoglobin. Other factors, including response to anemia, and the influence of infection with malaria and other environmental influences, may be important. The remarkable variation and instability of clinical phenotypes in Hemoglobin E thalassemia require individual management plans for each patient, which should be reassessed over time. Protein Quality Control During Erythropoiesis and Hemoglobin Synthesis 1071 Eugene Khandros and Mitchell J. Weiss Erythrocytes must regulate hemoglobin synthesis to limit the toxicities of unstable free globin chain subunits. This regulation is particularly relevant in b-thalassemia, in which b-globin deficiency causes accumulation of free a-globin, which forms intracellular precipitates that destroy erythroid precursors. Experimental evidence accumulated over more than 40 years indicates that erythroid cells can neutralize moderate amounts of free a-globin through generalized protein quality control mechanisms, including molecular chaperones, the ubiquitin-proteasome system, and autophagy. In many ways, b-thalassemia resembles protein aggregation disorders of the nervous system, liver, and other tissues, which occur when levels of unstable proteins overwhelm cellular compensatory mechanisms. Information gained from studies of nonerythroid protein aggregation disorders may be exploited to further understand and perhaps treat b-thalassemia. Anemia, Ineffective Erythropoiesis, and Hepcidin: Interacting Factors in Abnormal Iron Metabolism Leading to Iron Overload in b-thalassemia 1089 Sara Gardenghi, Robert W. Grady, and Stefano Rivella b-thalassemia is a genetic disorder caused by mutations in the b-globin gene and characterized by chronic anemia caused by ineffective erythropoiesis, and accompanied by a variety of serious secondary complications such as extramedullary hematopoiesis, splenomegaly, and iron overload. In the past few years, numerous studies have shown that such secondary disease conditions have a genetic basis caused by the abnormal expression of genes with a role in controlling erythropoiesis and iron metabolism. In this article, the most recent discoveries related to the mechanism(s) responsible for anemia/ineffective erythropoiesis and iron overload are discussed in detail. Particular attention is paid to the pathway(s) controlling the expression of hepcidin, which is the main regulator of iron metabolism, and the Epo/EpoR/Jak2/Stat5 signaling pathway, which regulates erythropoiesis. Better understanding of how these pathways function and are

3 ix altered in b-thalassemia has revealed several possibilities for development of new therapeutic approaches to treat of the complications of this disease. Iron Overload in Thalassemia and Related Conditions: Therapeutic Goals and Assessment of Response to Chelation Therapies 1109 John B. Porter and Farrukh T. Shah Transfusional iron loading inevitably results in hepatic iron accumulation, with variable extrahepatic distribution that is typically less pronounced in sickle cell disease than in thalassemia disorders. Iron chelation therapy has the goal of preventing iron-mediated tissue damage through controlling tissue iron levels, without incurring chelator-mediated toxicity. Historically, target levels for tissue iron control have been limited by the increased frequency of deferoxamine-mediated toxicity and low levels of iron loading. With newer chelation regimes, these limitations are less evident. The reporting of responses to chelation therapies has typically focused on average changes in serum ferritin in patient populations. This approach has three limitations. First, changes in serum ferritin may not reflect trends in iron balance equally in all patients or for all chelation regimens. Second, this provides no information about the proportion of patients likely respond. Third, this gives insufficient information about iron trends in tissues such as the heart. Monitoring of iron overload has advanced with the increasing use of MRI techniques to estimate iron balance (changes in liver iron concentration) and extrahepatic iron distribution (myocardial T2*). The term nonresponder has been increasingly used to describe individuals who fail to show a downward trend in one or more of these variables. Lack of a response of an individual may result from inadequate dosing, high transfusion requirement, poor treatment adherence, or unfavorable pharmacology of the chelation regime. This article scrutinizes evidence for response rates to deferoxamine, deferiprone (and combinations), and deferasirox. Pharmacologic Induction of Fetal Hemoglobin Production 1131 George Atweh and Hassana Fathallah Reactivation of fetal hemoglobin (HbF) expression is an important therapeutic option in adult patients with hemoglobin disorders. The understanding of the developmental regulation of g-globin gene expression was followed by the identification of a number of chemical compounds that can reactivate HbF synthesis in vitro and in vivo in patients with hemoglobin disorders. These HbF inducers can be grouped in several classes based on their mechanisms of action. This article focuses on pharmacologic agents that were tested in humans and discusses current knowledge about the mechanisms by which they induce HbF. Allogeneic Cellular Gene Therapy for Hemoglobinopathies 1145 Javid Gaziev and Guido Lucarelli Hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for patients with thalassemia major and sickle cell disease (SCD). Current myeloablative treatment protocols allow the cure of 78% to 90%

4 x of patients with thalassemia and 72% to 96% with SCD, depending on disease status at the time of transplantation. The major limitation to successful transplantation is the lack of a suitable HLA-matched family donor. Unrelated donor HSCT is now extensively used to treat thalassemia, with results similar to those obtained following transplantation using HLA-matched sibling donors. Patients who lack a matched related or unrelated donor can now benefit from successful transplantation using haploidentical donors. Umbilical Cord Blood Transplantation for Thalassemia Major 1165 Bindu Kanathezhath and Mark C. Walters Hematopoietic cell transplantation is curative therapy for thalassemia major. Although the clinical application of hematopoietic cell transplantation has relied on marrow collected from related and unrelated donors as the primary source of donor hematopoietic cells, umbilical cord blood (UCB) is an alternative source of hematopoietic cells and represents a suitable allogeneic donor pool in the event that a marrow donor is not available. Progress in developing UCB transplantation for thalassemia is reviewed and the most likely areas of future clinical investigation are discussed. Noninvasive Approaches to Prenatal Diagnosis of Hemoglobinopathies Using Fetal DNA in Maternal Plasma 1179 Y.M. Dennis Lo and Rossa W.K. Chiu Fetal DNA is present in the plasma of pregnant women and can be used for noninvasive prenatal diagnosis. Early work had focused on the detection of paternally inherited fetal mutations in maternal plasma. Recent advances in single-molecule counting approaches have allowed the mutation dosage of the fetus to be analyzed in maternal plasma. These developments have been demonstrated as feasible for noninvasive prenatal diagnosis of several hemoglobinopathies, including b-thalassemia and hemoglobin E disease. Hemoglobin GeneTherapy for b-thalassemia 1187 Arthur Bank Allogeneic stem cell transplantation currently is the only curative option for severe b-thalassemia and sickle cell disease. Human globin gene therapy with autotransplantation of transduced human hematopoietic stem cells is an exciting alternative approach to a potential cure. One patient with thalassemia has recently been reported to have clinical benefit after lentiviral human b-globin gene therapy. He has not required blood transfusions for almost 2 years. Most of the patient s gene correction and new human b-globin gene expression is caused by the expansion of a single clone in which the corrective transgene is inserted into an Hmga2 gene. BONUS ARTICLES 1203 Mouse Models of Inherited Cancer Syndromes 1205 Sohail Jahid and Steven Lipkin Animal models of cancer have been instrumental in understanding the progression and therapy of hereditary cancer syndromes. The ability to alter

5 xi the genome of an individual mouse cell in both constitutive and inducible approaches has led to many novel insights into their human counterparts. In this review, knockout mouse models of inherited human cancer syndromes are presented and insights from the study of these models are highlighted. Lower Gastrointestinal Tract Cancer Predisposition Syndromes 1229 Neel B. Shah and Noralane M. Lindor Although inherited predisposition to colorectal cancer (CRC) has been suspected for more than 100 years, definitive proof of Mendelian syndromes had to await maturation of molecular genetic technologies. Since the l980s, the genetics of several clinically distinct entities has been revealed. Five disorders that share a hereditary predisposition to CRC are reviewed in this article. Index 1253