Part I Hematopoiesis 1
Chapter 1 STEM CELL BIOLOGY[Thalia Papayannopoulou Ihor Lemischka] 1
Organization of Hematopoiesis 1
Emergence of Hematopoiesis and Relationship to Vascular Cells 3
Primitive and Definitive Hematopoiesis 5
Hematopietic Stem Cells 8
Chapter 2 HEMATOPOIETIC GROWTH FACTORS AND RECEPTOR[Kenneth Kaushansky] 25
Paradigms in the Hematopoietic Growth Factors and Receptiors 25
The Physiology of Specific Hematopoietic Growth Factors and Their Receptors 29
Hematopoietic Growth Factors in Pathological Conditions 48
Hematopoietic Growth Facetor Receptors in Hematological Disease 54
Chapter 3 TRANSCRIPTION FACTORS THAT REGULATE LINEAGE DECISIONS[Stuart H.Orkin] 80
Early Hematopoietic Development and Lineage Commitment:A Distinction 80
Identification of Relevant Genes and Thier Functional Analysis 81
Factors Required for Formation or Maintenance of the Earliest Progenitors of the hematopoietic Stem Cell 83
Factors Influencing Expansion of Immature Progenitors 85
Transcription Factors Required in One or Multiple Myeloerythroid Lineages for Lineage Selection or Cellular Maturation 86
Factors Required for the Development of Lymphoid Lineages 92
Possible Mechanisms of Lineage Selection 94
Chapter 4 SIGNAL TRANSDUCTION IN THE REGULATION OF HEMATOPOIESIS[James N.Ihle] 103
Introduction 103
Receptor Tyrosine Kinases 103
Cytokine Receptors and Janus Protein Tyrosine Kinases 105
Potential Regulators of Cytokine Receptor Siganling:JABs,SOCS,CIS 109
Substrates of Tyrosine Kinases 109
Regulatory Subunits of PI-3K 110
Phospholipases 111
TGF-βSignal Transduction 116
Chemokine Receptor Signal Transduction 117
Signal Transduction by the Frizzled Farmily of Receptors 118
Signal Transduction by the Death Domain-Containing and Related Receptors 118
NF-kB Activation 119
Bcl Family Members and Cytokine Signaling 121
Notch Receptor Signaling 122
IL-1 Receptor Mediated Signal Transduction 122
The MAP Kinase Cascade 123
Summary and Conclusions 125
Part II Red Cells 135
Chapter 5 HEMOGLOBIN SWITCHING[Gerge Stamatoyannopoulos Frank Grosveld] 135
Hemoglobin Production During Development 136
Mutations Affecting Switching 137
Regulation of the Globin Genes 141
The Locus Control Region 148
Molecular Control of Switching 153
Cell Biology of Switching 154
Fetal Hemoglobin in the Adult 158
Pharmacological Manipulation of Hemoglobin FSynthesis 162
Future Prospects 165
Chapte 6 THE THALASSEMISAS[D.J.Weatherall] 183
Historical Perspective 183
Definition and Classification 184
The Complexity of the Thalassemias:The Thalassemia Syndromes 186
αThalassemia 186
βThalassemia 199
The δβThalassemias 212
δThalassemia 215
εγδβThalessemia 216
Thalassemias for Which the Cause Has Not Been Determined 216
The Contord and Treatment of Thalassemias 216
Chapter 7 HUMAN HEMOGLOBINS:SICKLE HEMOGLOBIN AND OTHER MUTANTS[H.Fanklin Bunn] 227
Normal Human Hemoglobin 227
Humna Hemoglobin Mutants 234
Sickle Hemoglobin and Sickle Cell Disease 236
Hemoglobin Mutants With a Thalassemia Phenotype 259
The Unstable Hemoglobin Mutants (Congenital Heinz Body Hemolytic Anemia) 259
Hemoglobin Mutants With Abnormal oxygen Binding 261
M Hemoglobins 262
Introduction 275
Chapter 8 THE ERYTHROCYTE MEMBRANE AND CYTOSKELETON:STRUCTURE,FUNCTION,AND DISORDERS[Patrick G.Gallagher Edward J.Benz,Jr.] 275
Structure and Function of Cell Membranes 276
The Erythrocyte Membrane and Its Cytoskeleton 280
Biogenesis and Assembly of the Membrane During Red Cell Development 292
Disorders of Red Cell Membrane Lipids 293
Disorders of Red Cell Cytoskeletal Proteins 294
Molecular Defects Underlying Red Cell Membrane Protein Disorders 300
Summary and Conclusions 305
Chapter 9 RED CELL MEMBRANE ANTIGENS [Jonh B. Lowe] 314
The RH Blood Group System 314
The LW Blood Group System 319
Glycophorins A, B, and E and the MNSs Blood Group Locus 320
Glycophorins C and D and the Gerbich Blood Group Locus 320
The Kell Blood Group System 325
The Kidd Blood Group System 326
The Duffy(Fy)Blood Group System 327
The Lutheran Blood Group System 328
Complement System Proteins as Blood Group Determinants: The Chido/Rodgers Antigens and the Cromer-Related Antigens 329
The Complement Receptor I Protein and the Knops Blood Group Antigens 330
Polymorphism in Red Cell Acetylcholinesterase: The Cartwright Blood Group System 330
Polymorphism in Red Cell CD44: The Indian Blood Group System 330
Polymorphism in the Red Cell Water Channel Aquaporin-1: The Colton Blood Group System 330
Peptide Sequence Polymorphisms on Band 3, the Red Cell Anion Exchange Protein, and the Diego Blood Group System 331
Antigens on Uncharacterized Proteins 331
The ABO Blood Group Locus 331
The H and Se Blood Group Loci 339
The Lewis Blood Group Locus 342
The Ii Blood Group System 346
The P Blood Group System 347
Chapter 10 MOLECULAR BASIS OF IRON METABOLISM[Tracey A. Rouault Richard D. Klausner] 363
Iron Acquisition by Microorganisms 363
Overview of Human Iron Economy 364
Transferrin 365
The Transferrin Receptor 367
Ferritin 371
Cellular Iron Homeostasis 372
mammalian Iron Physiology 375
Mitochondrial Iron Homeostasis 380
Hereditary Hyperferritinemia and Bilateral Cataract Syndrome 381
Mechanisms of Tissue Damage by Iron 381
Perspectives and Future directions 381
Part III Lymphopoiesis 389
Chapter 11 GENE REARRANGEMENTS IN LYMPHOID CELLS [Ilan R. Kirsch W. Michael Kuehl] 389
Introduction 389
The Question of Immune Diversity 390
The Basis of Immune Diversity--A Generic Overview 390
The Mechanism of V(D)J Recombination 396
Regulation of Transcription 398
T-Cell Antigen Receptors 400
Immunoglobulins 405
Immune Receptor Gene Rearrangements as Markers of Clonal Proliferation 412
Immune Receptors as Participants in the Generation of Chromosomal Aberrations 416
The Use of Polymerase Chain Reaction to Follow Chromosomal Aberrations 424
Immune Receptor Gene Deletions/Alterations and Disease 424
Summary 424
Chapter 12 LYMPHOCYTE DEVELOPMENT[Gerald Siu] 431
Principles of Lymphocyte Development 431
Architecture of the Immune System 432
Defining Lymphocytes by Cell Surface Molecule Expression 434
Thymopoiesis 434
Peripheral Development of Mature T-Cell Subsets 442
B-Cell Development 444
Immunological Memory 449
Conclusions 451
Chapter 13 ANTIGEN PROCESSING AND T-CELL EFFECTOR MECHANISMS [Roger M. Pertmutter] 459
Antigen Processing and Presentation 460
Molecular Biology of the Human Leukocyte Antigen Complex 460
Antigen Processing:Presentation of Endogenously Synthesized Proteins 464
Allelic Variation in Major Histocompatibility Complex Genes 467
Architecture of the T-Cell Receptor 470
Recognition of Antigen by T Lymphocytes 470
The Biochemistry of T-Cell Signaling 472
T-Cell Effector Mechanisms 477
Summary 477
Part IV Myelopoiesis/White Blood Cell 485
Chapter 14 INTEGRINS IN HEMATOLOGY [Roy Zent David M. Rose Mark H. Ginsberg] 485
Integrins of Blood Cells 485
Integrin Structure 486
Integrin Signaling 487
Integrin Ligands in Hematology 491
Integrins in Hematopoiesis 493
Integrins in Leukocyte Trafficking 494
Integrins in Platelet Function 496
Integrins and Hematological Diseases 497
Chapter 15 CHEMOKINES AND THEIR RECEPTORS [David I. Jarmin Craig Gerard] 510
Overview of the Chemokine superfamily 510
CXC Chemokines 512
CC Chemokines 513
The C Subfamily 515
The CX3C Subfamily 515
Interspecies Homology and Function 515
Chemokine Receptors 515
Role of Chemokines in Normal Leukocyte Trafficking 520
Regulatory Control of the Expression of Chemokines and Their Receptors 521
Inflammatory Disease 522
Infectious Diseases 524
Chemokines as Regulators of Hematopoiesis 526
Angiogenesis, Cancer, and Chemokines 527
Animal Studies 528
Conclusions and Future Directions 528
Chapter 16 GENETIC DISORDERS OF PHAGOCYTE KILLING [John T. Curnutte Mary C. Dinduer] 539
Microbicidal Pathways in Phagocytes 539
The Respiratory Burst Oxidase 542
Chronic Granulomatous Disease 547
Hemolysis of Erythrocytes 564
Chapter 17 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA [Monica Bessler John P. Atkinson] 564
Diagnosis 564
The Glycosylphosphatidylinositol Anchor 570
The PIGA Gene 570
Future Directions 574
Part V Hemostasis 579
Chapter 18 VITAMIN K-DEPENDENT PROTEINS IN BLOOD COAGULATION [Johan Stenflo Bj?rn Dahlb?ck] 579
Introduction 579
Modular Organization of Vitamin K-Dependent Plasma Proteins 581
Gla-Containing Modules 583
Epidermal Growth Factor-Like Modules 592
Kringle Modules 596
A Module in Protein S With Thrombin-Sensitive Bonds 597
Serine Protease Modules 597
A Module in Protein S Resembling Sex Hormone-Binding Globulin 602
Introduction 614
Protein C 614
Chapter 19 THE PROTEIN C ANTICOAGULANT SYSTEM[Bj?rn Dahlb?ck Johan Stenflo] 614
Thrombomodulin 621
Cell Surface Receptors for Protein C and Activated Protein C 630
Protein S 631
C4b-Binding Protein 633
The Protein C Anticoagulant System, an Important Regulator of Blood Coagulation in Vivo 635
Molecular Genetics of Venous Thromboembolism 636
Tissue Factor Pathway Inhibitor 657
Chapter 20 REGULATION OF BLOOD COAGULATION BY PROTEASE INHIBITORS[George J. Broze, Jr. Douglas M. Tollefsen] 657
Antithrombin 662
Heparin Cofactor II 669
Chapter 21 HEMOPHILIA A, HEMOPHILIA B, AND VON WILLEBRAND DISEASE [J. Evan Sadler Earl W. Davie] 680
Factor VIII and Hemophilia A 680
Factor IX and Hemophilia B 691
von Willebrand Factor and von Willebrand Disease 697
Chapter 22 THE MOLECULAR BASIS OF FIBRIN [Russell F. Doolittle] 719
Fibrinogen: The Precursor of Fibrin 719
Fibrin Formation 723
Fibrinolysis 726
Fibrinogen Biosynthesis 728
Genetically Defective Fibrinogens 729
Molecular Ecology of Fibrinogen and Fibrin 732
Concluding Remark 733
Chapter 23 FIBRINOLYSIS AND THE CONTROL OF HEMOSTASIS [H. R. Lijnen D. Collen] 740
Introduction 740
Components of the Fibrinolytic System 741
Mechanisms of Fibrin-Specific Fibrinolysis 748
Pathophysiology of Fibrinolysis 750
Clinical Aspects of Thrombolysis 753
Chapter 24 PLATELETS [Philip W. Majerus] 764
Biology of Platelet Production 764
Physiology of Platelet Plug Formation 767
Platelet Membrane Receptors and Their Disorders 772
Von Willebrand Factor Receptor 774
Stimulus-Secretion Coupling in Platelet Activation 778
Platelet--Vessel Wall Interactions in the Control of Hemostasis 780
Part VI Molecular Oncology 791
Chapter 25 MOLECULAR ASPECTS OF ONCOGENESIS [Douglas R. Lowy Linda Wolff] 791
Introduction 791
Background:Tumor Viruses, Familial Cancers, and Cell Cycle Control 792
Cancer Is a Disease of Abnormal Growth 792
Oncogenes adn Proto-Oncogenes 799
Tumor Suppressor Genes 819
Cancer: Collaboration Among Genes That Regulate Growth 823
Future Directions 824
Chapter 26 MECHANISMS OF LEVKEMOGENESIS [Charles L. Sawyers Owen N. Witte] 832
Hematopoietic Growth Factors as Definitive Participants in Leukemogenesis 832
Receptor Alterations in Leukemogenesis 833
Intracellular Signaling Mechanisms 836
Ras-Controlled Pathways Are Key Intracellular Mediators of Leukemogenesis 840
Transcription Factor Translocations 841
Translocations in Genes Essential for Hematopoietic Development 843
Translocations in Genes That Affect Hematopoietic Differentiation 845
Translocations That Target Genes Involved in Homeotic Function 847
Translocations That Target Genes Affecting Apoptosis 848
Abnormalities in Genes Involved in Cell Cycle Progression 849
Summary 851
Part VII Viruses 861
Chapter 27 THE MOLECULAR AND BIOLOGICAL PROPERTIES OF THE HUMAN IMMUNODEFICIENCY VIRUS [Eric O. Freed Malcolm A. Martin] 861
Introduction 861
The Classification, Genomic Organization, and Proteins Encoded by Human Immunodeficiency Virus 861
The Virus Life Cycle: Overview 863
Molecular Biology of Human Immunodeficiency Virus Replication 867
Human Immunodeficiency Virus Life Cycle: Clinical Perspectives 888
Prospects for a Human Immunodeficiency Virus-I Vaccine 893
Chapter 28 VIRAL PATHOGENESIS OF HEMATOLOGICAL DISORDERS 916
B 19 PARVOVIRUSES[Neal Young] 916
The Parvoviruses 916
B19 Parvovirus 918
Epidemiology 923
Clinical Syndromes 924
Immune Response 927
Conclusion 929
RETROVIRUSES(HTLVs)[Mitsuaki Yoshida] 935
Introduction to Retroviruses 935
Human Retroviruses 936
HERPESVIRUSES[Eric Bruening Bill Sugden] 951
Structural Properties of Herpesviruses 952
Infection by Human Cytomegalovirus in Cell Culture 953
Latent and Lytic Infections by Herpesviruses 953
Infection by Epstein-Barr Virus in Cell Culture 955
Infections in the Human Host 956
Part VIII Gene Therapy 969
Chapter 29 GENE THERAPY FOR HEMATOPOIETIC DISEASES[Brian P. Sorrentino Arthur W. Nienhuis] 969
The Science of Gene Therapy for Hematopoietic Disorders 969
Disease-Specific Applications and Clinical Trials 983
SUMMARY 992
INDEX 1005