The Molecular Basis of Blood Diseases, 3rd Edition

This comprehensive text focuses on the pathophysiology of hematologic diseases. There is no field in which molecular techniques have been applied more fruitfully. Given the large amount of rapidly accumulating information in the field, this book fills a niche that will become increasingly important.

Each of the four editors is a distinguished investigator who has made important contributions to our understanding of blood disorders. Dr. George Stamatoyannopoulos is Professor of Medicine in the Division of Medical Genetics at the University of Washington School of Medicine in Seattle; Dr. Philip Majerus is Professor of Medicine and Biological Chemistry in the Division of Hematology/Oncology at the Washington School of Medicine in St. Louis; Dr. Roger Perlmutter is Executive Vice President of Basic Research at Merck Research Laboratories in Rahway, NJ; and Dr. Harold Varmus is President and Chief Executive Officer at Memorial Sloan-Kettering Cancer Center, and Professor of Cell Biology and Genetics at Cornell Medical School in New York. These giants in medicine, in turn, have assembled an outstanding group of contributors.

The book begins with a beautifully written chapter on stem cell biology that carefully describes the organization of hematopoiesis into stem cell compartments. An explanation of the general principles of hematopoietic stem cells, including their properties, identification, and purification, follows. The chapter concludes with a discussion of ex vivo expansion of hematopoietic stem cells, a potentially important strategy in stem cell transplantation.

In the second chapter, Dr. Ken Kaushansky, who has made numerous seminal observations regarding thrombopoiesis, describes hematopoietic growth factors and their receptors. The chapter also reviews the potential role of hematopoietic growth factors in the pathogenesis of various diseases, addressing, for example, the ability of erythropoietin to stimulate erythropoiesis and improve renal failure. The 5q- syndrome, a well-defined myelodysplastic syndrome, is described. Interestingly, the genes for many hematopoietic growth factors are located on the long-arm of chromosome 5. The role of excessive erythropoietin production in polycythemic states, of mutations in the thrombopoietin gene in patients with familial essential thrombocythemia, and of several cytokines including tumor necrosis factor in the pathogenesis of juvenile chronic myeloid leukemia are also addressed in this chapter.

The third chapter, by Dr. Stuart Orkin from Harvard Medical School, successfully presents the complicated subject of transcription factors so that it is understandable to the non-laboratory-based hematologist or oncologist. The chapter begins with a description of the transcription factors responsible for the development and maintenance of the early progenitors of the hematopoietic stem cell and then discusses the factors responsible for the commitment to myeloid and erythroid lineages. It concludes by addressing the factors responsible for the development of the lymphoid lineage.

As a natural progression, the following chapter by Dr. James Ihle discusses signal transduction as it pertains to hematopoiesis, concluding part I of the book. A large portion of the chapter is devoted to the activation of tyrosine kinase receptors and the consequences of phosphorylation of several substrates. This is particularly important as it provides a background for understanding the mechanism of action of the new bcr-abl tyrosine kinase receptor inhibitor imatinib mesylate (Gleevec) in patients with bcr-abl gene rearrangements, such as those with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

Part II focuses on red cells and comprises the next six chapters. Chapters 5 through 7 follow in logical sequence and are authored by four individuals (Drs. George Stamatoyannopoulos, Frank Grosveld, D. J. Weatherall, and H. Franklin Bunn) who have made important contributions to our understanding of hemoglobin production and regulation, the thalassemias and other hemoglobinopathies including sickle cell disease. Chapter 5, entitled "Hemoglobin Switching," also makes an otherwise complicated area quite understandable. The next two chapters focus on the erythrocyte, the structure of its membrane, disorders of red cell cytoskeletal proteins, and red cell membrane antigens.

Chapter 10 describes the important role of iron in all life forms. It discusses the transferring gene receptor, control of transferrin receptor synthesis, ferritin structure, iron-regulator proteins and disorders of iron hemostasis. An important section in this chapter concerns new information on the pathogenesis of hemochromatosis, given that the hemochromatosis gene was successfully cloned in 1996.

The third part of the book (chapters 11 through 13) covers lymphopoiesis, beginning with an important chapter on gene rearrangements in lymphoid cells. Both B- and T-cell gene rearrangements are described after a brief discussion on the structure of immunoglobulins. The chapter on lymphocyte development by Dr. Gerald Siu is particularly well-illustrated, graphically depicting the organization of the thymus, spleen, and lymph node.

Chapter 13 by Dr. Roger Perlmutter, on antigen processing and T-cell effector mechanisms, is one of the most complicated for the average reader-a consequence of the subject rather than the presentation, although it reflects important progress in our understanding of the immune system. Fortunately, this chapter is also well-illustrated.

Part IV shifts attention to myelopoiesis. It begins with a discussion of integrins and their role in signaled transduction and leukocyte trafficking, and includes an entire chapter on paroxysmal nocturnal hemoglobinuria. The latter chapter is beautifully written and describes the diagnostic techniques and pathophysiology of this rare but fascinating disease. Paroxysmal nocturnal hemoglobinuria serves as a paradigm for the impact of molecular biology on our understanding of the pathogenesis of hematologic disease. The condition is caused by a deficiency of the CD55 complement regulatory protein called decay-accelerating factor (DAF). Although most hematologists and oncologists will never see a case of paroxysmal nocturnal hemoglobinuria, this chapter gives the reader a genuine appreciation of the molecular basis of hematologic disease.

Part V is devoted to hemostasis. Our understanding of the molecular basis of the regulation of normal and perturbed hemostasis is welldescribed. Chapter 19 describes the importance of protein C and the coagulation cascade, as well as thrombomodulin and the thrombin-thrombomodulin complex-protein C interaction. The role of protein S in normal hemostasis is also elucidated. The chapter concludes with a discussion of the molecular genetics of venous thromboembolism including inherited activated protein C (APC) resistance, attributed to a single-point mutation in the FV gene, now referred to as factor V Leiden mutation. An important chapter on the hemophilias and von Willebrand disease, authored by Drs. J. Evan Sadler and Earl Davie, is included in this part of the book.

Chapter 22 is the first of several to address the fibrinolytic system, which frequently receives less attention than the procoagulant system. In chapter 23, entitled "Fibrinolysis and the Control of Hemostasis," Drs. H. R. Lijnen and D. Collen describe the components of the fibrinolytic system, including plasminogen, plasminogen activator, and plasminogen activator inhibitors. Primary disorders of the fibrinolytic system are uncommon, and the lack of familiarity with normal physiology of this system breeds intimidation for many clinicians. However, the reader will find these chapters very understandable while appreciating the complexity of the fibrinolytic system.

Dr. Philip Majerus authored the comprehensive chapter 24 on platelets. Many photomicrographs and schematic drawings complement the text.

Part VI focuses on the molecular basis of malignant hematologic diseases. The first chapter discusses the process of malignant transformation and begins with a description of the cell cycle and its control, followed by a section on abnormal cell growth. In chapter 26, Drs. Charles Sawyers and Owen Witte address leukemogenesis and include material on signal transduction and transcription factors. This excellent chapter contains several helpful tables that describe transcription factors as a consequence of chromosomal changes associated with specific hematologic malignancies. Also presented here is the story of the molecular pathogenesis of acute promyelocytic leukemia-perhaps the best example of how much molecular biology has taught us.

Part VII is dedicated to viruses and begins with a comprehensive description of the molecular and biological properties of the human immunodeficiency virus. The chapter is lengthy (793 references); however, it reflects the unprecedented amount of new information relating to this disease. Chapter 28, authored by Dr. Neal Young, addresses the viral pathogenesis of blood diseases. The remainder of part VII includes chapters on the various retroviruses and herpesviruses.

The final section of the text (part VIII) discusses the new field of gene therapy and its potential impact on the treatment of hematologic diseases. Although the promise of gene therapy has not yet been realized in the clinic, this chapter prepares the reader for possible future treatments.

The Molecular Basis of Blood Diseases has many strengths, including the distinction of the chapter authors, the natural flow and clear organization of the chapters, the many helpful illustrations and tables, and the comprehensive updated reference lists. Many sections may require rereading several times, reflecting the complexity of the field. In the end, the reader can’t help but feel inspired by the breadth of our understanding of blood diseases and the potential treatments that lie ahead.