血液病分子生物学 英文原版PDF电子书下载

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