HEMATOLOGY
Basic Principles and Practice​
Copyright
CONTENTS​
PART I MOLECULAR AND CELLULAR BASIS OF HEMATOLOGY.pdf
1
Anatomy and Physiology of the Gene
The Genetic View of the Biosphere: The Central Dogma of Molecular Biology
The Anatomy and Physiology of THE Gene
DNA and RNA Structure
Storage of Genetic Information in the Nucleotide Sequences of DNA
Transmission of Genetic Information to the Next Generation
The Expression of Genetic Information Via Translation Into Proteins Using the Genetic Code
Regulation of Gene Expression
Chromatin and the Epigenetic Regulation of Gene Expression
Regulatory Sequence Motifs in or Near Genes: Enhancers, Promoters, and Silencers
Transcription Factors
Regulation at the Level of Pre-mRNA and mRNA Metabolism
Pre-mRNA Splicing
Modification of the Ends of the mRNA Molecule
5' and 3' Untranslated Sequences Within mRNAs That Modulate Stability and Translatability
Transport of mRNA From Nucleus to Cytoplasm: mRNP Particles
Regulation of mRNA Processing and Stability
Regulation at the Level of mRNA Translation
Heterogeneity of rRNAs and tRNAs
Roles of Small Interfering RNAs, Micro RNAs, Short Hairpin RNAs, and Long Noncoding RNAs in Regulating Gene Expression
Some Illustrative Structural Features of the Genome Relevant to Hematology
Polymorphism and Single Nucleotide Polymorphisms
Repeated Sequence Motifs
Molecular Genetic Methodologies Allowing the Isolation, Analysis, and Manipulation of Genes
The Polymerase Chain Reaction
High-Throughput DNA and RNA Sequencing
Gene Cloning
Use of Transgenic and Knockout/Knockin Organisms to Model Gene Function
DNA- and RNA-Based Therapeutics
Gene Therapy and Gene Editing
RNA Therapeutics
Future Directions
Suggested Readings
2
Epigenomics in Hematology
Functional Chromatin Domains
Dna Methylation
Histones And Histone Variants
Covalent Histone Modifications
Transcription Factors
Chromatin Remodelers
Experimental Approaches in Epigenetics
Mechanisms of Disease
Epigenetic Therapies
Future Directions
Suggested Readings
3-s2.0-B978032373388500002X
3
Genomic Approaches to Hematology
Introduction
General Principles of Genomic Testing
Genomic Analysis
The Importance of Sample Quality
Analytical Considerations
Next-Generation Sequencing Technology
RNA Profiling
Noncoding RNA
Mutation Detection Strategies
Germline Versus Somatic Variants
Point Mutations or Single Nucleotide Variants
Structural Variation
Copy Number Abnormalities
Chromosomal Rearrangements
Epigenomics
The Clinical Utility of Genomics in Hematologic Malignancies
Diagnosis
Precision Medicine and Molecularly Targeted Therapies
Risk-Stratified Therapy
Response-Adapted Therapy and Minimal Residual Disease Monitoring
Pharmacogenomics
The Clinical Utility of Genomics in Benign Hematology
The Hemoglobinopathies
Clotting Disorders
Disease with Rare Penetrant Variants Involving Multiple Loci
Common Low Penetrance Risk Variants
Approaches to the Development of Molecular Testing
Suggested Readings
References
4
Regulation of Gene Expression in Hematology
Introduction
Regulation of Transcription
RNA Polymerase Binding and Regulation by Transcription Factors
Regulation of Transcription by Chromatin
Regulation of Transcription by DNA Modification
RNA Proofreading
Regulation of RNA Processing: Capping, Splicing, and Polyadenylation
Nuclear Export of RNA
RNA Heterogeneity
Regulation of RNA Metabolism: Stability and Localization
Regulation of RNA Stability by 5' and 3' UTR Sequences and Structures
Nonsense-Mediated Decay
RNA Modifications: The Epitranscriptome
RNA Interference
RNA Granules and Membraneless Organelles
Protein Synthesis
The Process of Translation
Ribosome Disorders
Protein Sorting
Targeting of Nuclear Proteins
Cotranslational Protein Translocation Into the Endoplasmic Reticulum
Intra-Golgi Transport and Protein Processing
Sorting Into Lysosomes
Targeting of Mitochondrial Proteins
Targeting of Peroxisomal Proteins
Sorting into Regulated Secretory Granules
Protein Folding and Posttranslational Modifications
Protein Folding
Protein Modifications
Protein Folding and Modifications in the Endoplasmic Reticulum
Protein Degradation
Endoplasmic Reticulum-Associated Degradation and the Unfolded Protein Response
Protein Degradation by the Proteasome
Conclusions
Suggested Readings
References
5
Genome Editing
Double-Stranded Dna Breaks: The Basis of Nuclease-Based Genome Editing
Base Editing
Other Genome Editing Systems
Using Engineered Nucleases to Initiate the Genome Editing Process
Genome Editing Using Only a Nuclease And Nonhomologous End-Joining Repair
A Broad Range of Genomic Changes by Homologous Recombination–Mediated Genome Editing
Genotoxicity Through Potential Off-Target Nuclease-Induced Double-Strand Breaks
Genome Editing As a Research Tool
Genome Editing As a Therapeutic Strategy
Ex Vivo Manufacturing of Therapeutic Cells
Therapeutic Genome Editing for Hematologic Diseases
Sickle Cell Disease
Fetal Hemoglobin Derepression
Direct Gene Correction
β-Thalassemia
Fetal Hemoglobin Derepression
Knocking HBB into HBA1
Primary Immunodeficiency Diseases
Using the Blood System to Treat Nonhematologic Diseases (Metabolic Diseases)
Genome Editing of Immune Effector Cells for Safer and More Potent Cancer Therapies (CAR-T Cells)
Off-the-Shelf CAR-T Cells
Increasing Potency
Opportunities for Genome Editing in Vivo
Challenges to in Vivo Editing of Hematopoietic Stem Cells
Delivery
Immunogenicity
Heritable Genome Editing
Suggested Readings
References
6
Signaling Transduction and Metabolomics
Signaling Transduction
Receptor Tyrosine Kinases, Phosphoinosite-3-Kinase, and Mitogen-Activated Protein Kinase Pathways
Receptor Tyrosine Kinases
Phosphatidylinositol 3-Kinase Pathway
MAPK/ERK Pathway
The Transforming Growth Factor-β Pathway
Signaling Through Receptors Associated With Protein-Tyrosine Kinases
Cytokine Receptors and Janus-Activated Kinase Signaling
Multichain Immune Recognition Receptors
Integrin Signaling
Tumor Necrosis Factor Receptors and Signaling
Toll-Like Receptors and Signaling
Wnt Signaling
Notch Signaling
Hedgehog Signaling
Nuclear Hormone Receptor Superfamily
G Protein–Coupled Receptor and Chemokine Signaling
G Protein–Coupled Receptor Signaling
Chemokine Signaling
cGAS–cGAMP–STING Signaling Pathway
Endoplasmic Reticulum Stress Signaling Pathways
Heme Signaling Transduction
Hypoxia Signaling Transduction
Metabolomics and Control of Hematopoietic Cell Metabolism
Glucose Metabolism
Glycolysis
Pentose Phosphate Pathway
Tricarboxylic Acid or Krebs Cycle
Oxidative Phosphorylation
Reactive Oxygen Species Metabolism
Lipid Metabolism
Fatty Acid Synthesis
Fatty Acid Oxidation
Cholesterol
Phospholipids
Amino Acid Metabolism
Biosynthesis of Nonessential Amino Acids
Amino Acid Catabolism
Nucleotide Metabolism
Nucleotide Synthesis
Nucleotide Degradation
Introduction to Metabolomics
Metabolomics of Glucose Metabolism
Metabolomics of Lipid Metabolism
Metabolomics of Nucleotide Metabolism
Metabolomics of Amino Acid Metabolism
Summary and Perspectives
Suggested Readings
7
Protein Architecture: Relationship of Form and Function
Amino Acids And The Peptide Bond
Protein Secondary Structure
Posttranslational Modifications
The Domain Structure of Proteins
The Immunoglobulin Domain and Variations
The Protein Kinase Domain
Membrane Proteins
Future Directions
Suggested Readings
References
8
Pharmacogenomics and Hematologic Diseases
Variation in the Human Genome
Single-Nucleotide Polymorphisms
Single-Nucleotide Polymorphisms and Phenotypes
Structural Genomic Variants
Somatic Genomic Variants
Catalogs of Genomic Variants, Genotyping Platforms, and Genome-Wide Association Studies
Variation in the Human Epigenome
Genetic Variations Influencing Drug Response: Pharmacogenetics–Pharmacogenomics–Pharmacoepigenomics
Optimization of Drug Therapy
Genetic Variations That Influence Drug Disposition and Effects
Drug Metabolism and Effects
Pharmacogenomics of Thiopurines in Childhood Leukemia
MP Dosage Adjustment According to the CPIC Guidelines Based on TPMT and NUDT15 Genotypes in Acute Lymphoblastic Leukemia
Relapse of Acute Lymphoblastic Leukemia, Thiopurine Resistance, and Somatic Variants in NT5C2 and PRPS1
Glucocorticoid Pharmacogenomics in Childhood Acute Lymphoblastic Leukemia
Inherited Genome Variants in Cytochrome P450 Enzymes
Pharmacogenomics of Warfarin
Drug Transporters
SLCO1B1 and Methotrexate
Genetic Variations Influencing Drug Targets
BCR-ABL1 and Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia
Adverse Drug Effects Presenting as Hematologic Disorders
Glucose-6-Phosphate Dehydrogenase Deficiency and Rasburicase
Drug Development
Drug Development in Pediatric High-Risk B-Cell Acute Lymphoblastic Leukemia
Identification of Novel Therapies for KMT2A-Rearranged Infant ALL
Identification of Novel Therapies for “BCR-ABL1–Like” ALL
Future Directions
Suggested Reading
References
PART II CELLULAR BASIS OF HEMATOLOGY.pdf
Chapter
9
Hematopoietic Stem Cell Biology
Embryonic Origin of Hematopoietic Stem Cells
Definition and Characterization of Hematopoietic Stem Cells
Phenotype
Murine Hematopoietic Stem Cells
Human Hematopoietic Stem Cells
CD49f+ Human Hematopoietic Stem Cells
Functional Characterization
In Vitro Assays
In Vivo Assays
Colony-Forming Unit–Spleen Assays
Competitive Repopulation Assays
Clonal Dynamics of Hematopoietic Stem Cells
Regulation of Hematopoietic Stem Cell Fate
Extrinsic Regulation
NOTCH Signaling
WNT Signaling
Transforming Growth Factor-β and Hedgehog Signaling
CXCL12–CXCR4 Signaling
Intrinsic Pathways
Transcription Factors
Transcription Factors Required for the Specification of Hematopoietic Stem Cells
Transcription Factors Required for Hematopoietic Stem Cell Homeostasis
The Homeobox Cluster in Hematopoietic Stem Cell Self-Renewal
Transcription Factor Networks
Epigenetic Regulation of Hematopoietic Stem Cell Self-Renewal
Regulation of Hematopoietic Stem Cells by Noncoding RNAs
Hematopoietic Stem Cell Metabolism
Novel Growth Factors For Expanding Hematopoietic Stem Cells and Clinical Testing
Generating Hematopoietic Stem Cells From Pluripotent Stem Cells and by Reprogramming of Somatic Cells
Hematopoietic Stem Cell Regeneration
Hematopoietic Stem Cells and Malignancy (See Chapters 13 and 59)
Suggested Readings
References
10
Mitochondria and Hematopoiesis
Mitochondrial Structure and Function
Mitochondrial Diseases
Mitochondrial Regulation of Hematopoietic Stem Cell Fates
The Mitochondrial Unfolded Protein Response Mechanism
The Mitochondrial Oxidative Self-Defense Response Mechanism
Mitochondrial Dynamics Controls the Self-Renewing Potential of Hematopoietic Stem Cells
Mitophagy as a Gatekeeper of Hematopoietic Stem Cells Fate Decisions
Mitochondrial Metabolic Regulation of the Epigenetic Landscape of Hematopoietic Stem Cells
Interaction Of Mitochondrial Network With The Bone Marrow Milieu Regulates Hematopoietic Stem Cell Fates
Mitochondrial And Bone Marrow Roles In Leukemic Stem Cells And Aged Hematopoietic Stem Cells
Mitochondrial and Epigenome Control Reprogramming Of Hematopoietic Stem Cells
Concluding Remarks
References
11
Cytokines, Chemokines, Other Growth Factors, and Their Receptors
Introduction
Cytokines And Their Modifying Influences
Specifics Of Growth-Modulating Factors
Colony-Stimulating Factors
Interleukins
Chemokines and Chemokine Receptors
Role of Nuclear Factor-κB in Cytokine and Chemokine Gene Regulation, Inflammation, Immunity, and Cancer
Engineered Cytokines and Role of Cytokines and Other Reagents for Preclinical and Clinical Ex Vivo Expansion of Hematopoiet ...
Other Growth Modulating Proteins/Factors
Iron-Binding Proteins
Transforming Growth Factor-β, Associated-Inhibin Family Members, Bone Morphogenic Protein, Tumor Necrosis Factor-α, and Int ...
Transforming Growth Factor-β
Inhibins (Activin and Inhibin)
Bone Morphogenetic Protein
Tumor Necrosis Factor
Interferons
Additional Growth Modulating Factors
Prostaglandin E
Enzymes, Matrix Metalloproteinases, and Dipeptidylpeptidase 4, as Modifiers of Cytokine/Chemokine Biologic Activities
Microenvironmental Niche and Role of Oxygen Tension in Hematopoiesis
Exosomes/Extracellular Vesicles
Aging in Context of Cell Regulation
Radiation Effects on Hematopoiesis
Concluding Thoughts
Suggested Readings
References
12
Role of Chemokines in Leukocyte Trafficking​
Chemokines
Signaling by Chemokine Receptors
Atypical Chemokine Receptors
Chemokine Interaction With Glycosaminoglycans
Leukocyte Entry Into Tissues
Chemokine Control of Lymphocyte Homing to Secondary Lymphoid Organs
Trafficking of Leukocytes From Blood Into Nonlymphoid Tissues
Migration of Hematopoietic Stem Cells to the Bone Marrow and Mobilization in the Niche
Leukocyte Migration Within Tissues
Trafficking Patterns of Lymphocytes
Migration of T Cells to T Zones Within Secondary Lymphoid Organs
Positioning of B Cells Within Secondary Lymphoid Organs
Leukocyte Exit From Tissues
Reprogramming Dendritic Cells to Exit Tissues Toward Secondary Lymphoid Organs
Egress of Lymphocytes From Secondary Lymphoid Organs
Summary
References
Suggested Readings
13
Stem Cell Model of Hematologic Diseases
Cell-Of-Origin Studies In Hematologic Malignancies
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Myeloproliferative Neoplasms
Acute Lymphoblastic Leukemia
Mature B-Cell Malignancies
Chronic Lymphocytic Leukemia
Hairy Cell Leukemia
Diffuse Large B-Cell Lymphoma
Follicular Lymphoma
Conclusion
References
14
Hematopoietic Microenvironment
Evolution of The Niche Concept
Hematopoietic Microenvironment During Development
Adult Bone Marrow Microenvironment
Hematopoietic Stem Cell Niches
Location of the Hematopoietic Stem/Progenitor Cell Niche
Cellular Components of the Hematopoietic Stem/Progenitor Cell Niche
Osteolineage Cells
Endothelial Cells
Perivascular Cells
Adipocytes
Osteoclasts
Bone Marrow Macrophages
Megakaryocytes
Extrinsic Regulation of the Hematopoietic Stem Cell Niche
Sympathetic Innervation
Hypoxia
Niche Contribution to Leukemia Development
Niche Alterations by Leukemia
Therapeutic Targeting of Leukemic Niche
Lymphoid Niches
Erythroid Niches
Megakaryocytic Niches
Human Bone Marrow Microenvironment
Hematopoietic Microenvironment in Acute Leukemia and Myelodysplasia
Future Directions
References
15
Cell Adhesion
Adhesion Molecules
Extracellular Matrix Proteins
Integrins
Immunoglobulin-Like Receptors
Other Adhesion Receptors that Mediate Protein–Protein Interactions
Lectin Adhesion Receptors
Ligand Binding Versus Cell Adhesion
Regulation of Adhesion Receptors
Regulation of Synthesis
Regulation of Surface Expression
Regulation of Binding Affinity
Cell Signaling Through Adhesion Molecules
Cooperative Interactions Between Signaling and Adhesion Molecules
Platelet Adhesion, Aggregation, and Hemostasis
Leukocyte Rolling, Spreading, and Migration Across Vascular Endothelium During Inflammation
Adhesion of T Cells to Antigen-Presenting Cells during Antigen Priming
Genetic Deficiencies in Adhesion Molecules
Dysregulated Expression of Adhesion Molecules
Suggested Readings
16
Current Biology of Stem Cell Homing and Mobilization: Dynamic Interactions Between Hematopoietic Stem and Progenitor Ce ...
Introduction
Lessons from Steady-State Homeostatic Regulation of Hematopoietic Stem and Progenitor Cells
Daily Light- and Darkness-Onset Induced Signals Maintain Blood Replenishment Together With Self-Renewal of Long-Term Repopu ...
Mechanisms of Long-term Repopulating Stem Cell Chemotherapy Resistance via Anchorage to Their Supportive Bone Marrow Niches ...
Hematopoietic Stem and Progenitor Cell Regulation via Dynamic Interactions With the Blood-BM Endothelial Barrier and the St ...
Medical Approaches Originating from Understanding Mechanisms that Regulate Physiological Hspc Trafficking, for the Sake of ...
Establishment of Functional Preclinical Immune-Deficient Mice Models to Study Human Hematopoietic Stem Cell Trafficking and ...
Hematopoietic Stem and Progenitor Cell Homing
The Essential Role of the CXCL12/CXCR4 AXIS in the Regulation of Hematopoietic Stem and Progenitor Cell Homing
Hematopoietic Stem and Progenitor Cell Mobilization: A Dynamic Multi-Facet Process
The CXCL12/CXCR4 Axis as a Driving Force Leading to Hematopoietic Stem and Progenitor Cell Mobilization
Dynamics of the Hematopoietic Stem and Progenitor Cell Niches and the Bone Marrow Microenvironment During Mobilization
Concluding Remarks
Acknowledgments
References
17
Control of Cell Division
The Cell Division Cycle
Quiescence and Differentiation
G1 Phase
S Phase
G2 Phase
M Phase
Signaling
T-Cell Receptor
B-Cell Receptor
Macrophage Colony-Stimulating Factor Receptor
RAS Pathway to Cyclin D
Cyclins and Cyclin-Dependent Kinases
Cyclin-Dependent Kinase Inhibitors
Transcriptional Regulation: MYC, RB-E2F, And Dream/Muvb
Ubiquitination
Deoxyribonucleic Acid Replication
Mitosis
Cell Cycle Checkpoints
Competence
Restriction Point
G1/S Checkpoint
S Phase Checkpoint
G2/M Checkpoint
Senescence
Spindle Assembly Checkpoint
Special Hematology Cell Cycle Features
Hematopoietic Stem Cells
Endoreplication
References
18
Cell Death
Core Apoptosis Pathways
The Intrinsic Apoptotic Pathway
Nonapoptotic Roles Of Bcl-2 Family Proteins
The Death Receptor (Extrinsic) Pathway Of Apoptosis
Nonapoptotic Forms Of Cell Death
Necroptosis
Ferroptosis
Pyroptosis
Cell Survival And Cell Death Pathways And Adaptive Responses To Stress
Autophagy
Unfolded Protein Response
Clinical Applications
Preclinical Activity Of Bcl2 Antisense And Bh3-Mimetics In Myeloid Malignancies
Preclinical Activity of Oblimersen in Acute Myeloid Leukemia
Preclinical Activity of Obatoclax in Acute Myeloid Leukemia
Preclinical Activity of Navitoclax and ABT-737 in Acute Myeloid Leukemia
Preclinical Activity of Single-Agent Venetoclax in Acute Myeloid Leukemia
Combination Strategies to Boost Venetoclax Activity and Overcome Venetoclax Resistance
Novel Venetoclax-Based Combinations
Clinical Development Of Bh3-Mimetics For Myeloid Malignancies
Clinical Development of Oblimersen for Acute Myeloid Leukemia
Clinical Development of Obatoclax for Acute Myeloid Leukemia
Clinical Development of Venetoclax for Acute Myeloid Leukemia
Rationale For Use Of Bh-3 Mimetics In Chronic Lymphocytic Leukemia
Clinical Development Of Venetoclax For Chronic Lymphocytic Leukemia
Mechanisms Of Resistance To Venetoclax In Chronic Lymphocytic Leukemia
Summary
Suggested Readings
References
19
Aging and Hematopoiesis
Aging
Hematopoietic Stem Cell Potential Declines With Aging
Clinical Manifestations
Anemia
Immunosenescence
Myelodysplastic Syndromes
Leukemia
Clonal Hematopoiesis, Clonal Hematopoiesis Of Indeterminate Potential, And Age-Related Clonal Hematopoiesis
Mechanisms Of Hematopoietic Stem Cell Aging
Intrinsic Factors
DNA Damage
Autophagy and Reactive Oxygen Species
Epigenetic Modifications
Chromatin Architecture and Polarity
Extrinsic Factors
Bone Marrow Microenvironment
Senescence
Inflammation
Future Perspectives
References
PART III IMMUNOLOGIC BASIS OF HEMATOLOGY.pdf
20
Dendritic Cell Biology
Dendritic Cell Subsets And Development
Conventional Dendritic Cells
Plasmacytoid Dendritic Cells
Inflammatory Dendritic Cells
Langerhans Cells
New Developments in Dendritic Cell Classification
Dendritic Cell Maturation
Antigen Processing And Presentation
MHC Class I Antigen Presentation (Endogenous Route)
MHC Class II Antigen Presentation (Exogenous Route)
Cross-Presentation
Dendritic Cell-Mediated Immune Responses
T Cells
B Cells
Innate Lymphoid Cells
Other Elements of the Immune System
Dendritic Cells In Disease
Dendritic Cells and Autoimmunity
Dendritic Cells and Immunodeficiency
Dendritic Cells and Pathogens
Dendritic Cells And Cancers
Immunotherapeutic Strategies And Clinical Trials
Future Directions
Suggested Readings
References
21
Natural Killer Cell Immunity AND THERAPY
Natural Killer Cell Fundamental Biology
Natural Killer Cell Subsets
CD56dim Natural Killer Cells
CD56bright Natural Killer Cells
Natural Killer Cell Development
Natural Killer Cell Receptors
Killer-Cell Immunoglobulin-Like Receptors
C-Type Lectin Receptors
Natural Cytotoxicity Receptors
Other Activating Receptors
Adaptive Immune Properties Of Natural Killer Cells
Natural Killer Cell Education
Natural Killer Cell Memory
The Role Of Natural Killer Cells In Human Disease
Natural Killer Deficiency Syndromes Linked to Increased Infectious Risks
The Role of Natural Killer Cells in Autoimmunity
The Therapeutic Potential Of Natural Killer Cells
Natural Killer Cells and Hematopoietic Cell Transplantation
Infusion of Autologous Natural Killer Cells
Infusion of Allogeneic Natural Killer Cells
Expansion of Natural Killer Cells In Vivo via Cytokine Administration
Killer-Cell Immunoglobulin-Like Receptors Blockade
Natural Killer Cell Checkpoint Blockade
Natural Killer Cell Antibody-Dependent Cytotoxicity
Genetic Engineering of Natural Killer Cells
Future Directions
Suggested Readings
References
22
B-Cell Development
Stages of B-Cell Development
Murine B-Cell Development
Human B-Cell Development
B Lineage Specification and Commitment
Transcriptional Regulation of B-Cell Development
MicroRNAs
Immunoglobulin Gene Rearrangement
Heavy Chain Gene Rearrangement
Light Chain Gene Rearrangement
The Immunoglobulin Recombinatorial Machinery
Generation and Selection of the Primary B-Cell Repertoire
The Pro-B- and Pre-B-Cell Checkpoints
The Pro-B- to Pre-B-Cell Transition
The Pre-B to B-Cell Transition
The B-Cell Receptor
The Hematopoietic Microenvironment
Fetal B-Cell Development
B-1 B Cells
Secondary Lymphoid Tissues
Anatomic Organization of Secondary Lymphoid Tissues
Transitional B Cells
Immune Responses in Secondary Lymphoid Tissues
Germinal Centers
Immunoglobulin Class Switching and Affinity Maturation
Effects of Aging on B-Cell Development and Function
References
23
Complement And Immunoglobulin Biology Leading To Clinical Translation​
The Complement System: An Overview
Classical Pathway
Lectin Pathway
Alternative Pathway
C3, C5, and the Membrane Attack Complex
Complement Receptors and Their Role in Immune Complex Clearance and Activation
Biologic Activity of C3a and C5a
Regulation of Complement Activation
Biologic Consequences of Complement Cascade Deficiencies
Biologic Consequences of Complement Regulatory Protein Deficiencies and Function-Affecting Mutations
Autoimmunity and Complement Deficiencies
Natural Antibody
Complement Links Innate and Adaptive Immune Responses
Soluble Complement Mediators of Antibody Responses
Complement Receptors and Antibody Responses
B-Lymphocyte Coreceptors
Focusing Antigen on Follicular Dendritic Cells
Complement and T-Cell Immunity
Complement and Cancer
Complement and Coagulation
Conclusion
Immunoglobulins
Properties and Structure
Therapeutic Use Of Immunoglobulin
Intravenous Immunoglobulin
Adverse Events Related to Intravenous Immunoglobulin Infusion
Early Systemic Events
Infectious Disease Transfer
High-Dose Treatment–Related Adverse Events
Therapeutic Passive Immunization and Monoclonal Antibody Therapy
Drugs Targeting The Complement System
Eculizumab
Ravulizumab
New Anticomplement Drugs: Pegcetacoplan and Beyond
References
Suggested Readings
24
T-Cell Immunity
T-Cell Activation
Antigen Presentation: Creating the Ligand for the T-Cell Receptor
The T-Cell Receptor Complex
T-Cell Receptor Signal Transduction
Co-Stimulation
Spatial Coordination of T-Cell Receptor Signal Transduction: The Immunologic Synapse
T-Cell Proliferation
T-Cell Development
Early T-Cell Development
Positive Selection
CD4 and CD8 Lineage Commitment
Negative Selection
T-Cell Function
Th1 Cells
Th2 Cells
Th17 Cells
Tfh Cells
CD4+ Th Plasticity
CD8+ Cytotoxic T Cells
Maturation Of T-Cell-Mediated Immunity
T-Cell Memory
T-Cell Exhaustion: Impaired Response after Chronic Antigen Exposure
Inhibition Of T Cell-Mediated Immunity
Prevention of Inappropriate Initiation of T-Cell Responses
Anergy
Regulatory T Cells
Limiting T-Cell Responses After Stimulation by Foreign Antigen
Limitation of T-Cell Activity from Cell-Intrinsic Components
Protein Tyrosine Phosphatases
Cytotoxic T Lymphocyte Antigen-4
E3 Ubiquitin Ligases
Diacylglycerol Kinases
Limitation of T-Cell Activity From Cell-Extrinsic Components
Terminating Immune Responses After Pathogen Clearance
Therapeutic Manipulation Of T-Cell-Mediated Immunity
Modulating T Cells to Permit Allograft Transplantation
Manipulating T Cells to Improve Activity Against Malignancy
Suggested Readings
References
25
Unmodified Ex Vivo Expanded T Cells
Adoptive Immunotherapy of Viral Infections with Virus-Specific T Cells
Methods to Generate Virus-Specific T Cells
Rapid Selection
Ex Vivo Expansion
Off-the-Shelf T-Cell Banks
Adoptive Immunotherapy Of Cancer
Adoptive Immunotherapy of Virus-Associated Malignancies
Adoptive Immunotherapy of Virus-Independent Malignancies
Neoantigens
Mismatched Histocompatibility Antigens
Non-Histocompatibility, Germline Antigens
Future Directions
Suggested Readings
References
26
Treatment of Hematologic Malignancies With Genetically Modified T Cells
Types of Cellular Immunotherapy
Adoptive Cell Therapy With T Lymphocytes
Allogeneic Donor Lymphocyte Infusion
Infusion of Activated T Lymphocytes
Genetic Modification of T Cells
Artificial αβT-Cell Receptors
Chimeric Antigen Receptors
Clinical Results of Chimeric Antigen Receptor T Cells in Hematologic Malignancies
CD19
B-Cell Maturation Antigen
CD30
Acute Myeloid Leukemia Targets
T-Cell Antigens
Factors Affecting Response
Toxicities of Chimeric Antigen Receptor T Cells
Allogeneic Banked Cells
Optimizing T-Cell Trafficking and Overcoming Tumor Immune Evasion
T Lymphocytes, Transfer of Safety Genes, and Strategies to Improve Tumor Cell Specificity
Future Applications and Implementation of Cell Therapies for Cancer
ACKNOWLEDGMENT
References
PART IV DISORDERS OF HEMATOPOIETIC CELL DEVELOPMENT.pdf
27
Biology Of Erythropoiesis, Erythroid Differentiation, And Maturation
Erythroid Cell Compartments
Phenotypic and Functional Properties of Erythroid Progenitor Cells
The Morphologically Recognizable Erythroid Precursor Cell Compartment
Plasma Membrane and Cytoskeleton Reorganization
Mitophagy and Ribosome and Mitochondria Clearance
Nuclear Condensation and Enucleation
Intrinsic Control of Erythropoiesis
Extrinsic Control of the Erythropoiesis
Erythropoietin
Hematopoietic Microenvironment
Erythropoiesis and Iron Regulation
Cellular Dynamics in Erythropoiesis: Steady State and Stress Erythropoiesis
Ontogeny of Erythropoiesis
Erythroid Cells from in Vitro Generated Sources
Suggested Readings
References
28
Granulocytopoiesis and Monocytopoiesis
Granulocytopoiesis
Granulocyte Ontogeny
Stages of Neutrophil Differentiation
Markers of Granulocytic Maturation
Neutrophil Granules and Their Content Proteins
Control of Granulopoiesis
Cytokine Regulation of Myeloid Proliferation and Differentiation
Transcriptional Regulation of Myeloid Differentiation
Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression
Runx1
CCAAT Enhancer-Binding Protein Family of Transcription Factors.
C/EBPα
C/EBPβ
C/EBPβ in Emergency Granulopoiesis
Transcriptional Networks in Emergency Granulopoiesis
C/EBPγ
C/EBPδ
C/EBPε
C/EBPζ
PU.1
Growth Factor Independence-1
CCAAT Displacement Protein
Role of Developmentally Important Neutrophil-Specific Genes In Disease
Severe Congenital Neutropenia and the Unfolded Protein Response
Role of MicroRNAs in Controlling Gene Expression in Granulopoiesis
Eosinophil Production
Basophil and Mast Cell Production
Monocytopoiesis
Monocyte Ontogeny
Stages of Monocyte Differentiation
Markers of Monocyte Maturation
Control of Monocytopoiesis
Cytokine Regulation of Monocyte Proliferation and Differentiation
Transcriptional Regulation of Monocyte Differentiation
c-Jun
Other Transcription Factors Modulating Monocyte Development
Egr-1.
C/EBPβ.
MafB and c-Maf.
Suggested Readings
References
29
Thrombocytopoiesis
Megakaryocyte Biology
Megakaryocytopoiesis
Cellular Hierarchy of Megakaryocyte Development
Relationship Between Megakaryocytes and Hematopoietic Stem Cells
Unique Features Of Megakaryocytes
Endomitosis and Polyploidization
The Endomitotic Cell Cycle
Role of Endomitosis in Thrombocytopoiesis
Mechanisms of Endomitosis in Megakaryocytes
Cyclins and Cyclin-Dependent Kinases
Other Mitotic Kinases
Microtubules and the Mitotic Spindle
The Spindle Checkpoint.
Contractile Ring Activity
Platelet Biogenesis
Megakaryocytopoiesis in Ontogeny
Tissue Distribution and Spatial Cues During Megakaryocytopoiesis
Therapeutic Applications of Ex Vivo Megakaryocytopoiesis
Cytokine Regulation Of Thrombocytopoiesis
Thrombopoietin Signaling
Thrombopoietin
Thrombopoietin Receptor (c-Mpl)
Thrombopoietin Receptor Downstream Signaling Pathways
Negative Regulation of Thrombopoietin Signaling
Regulation of Platelet Mass by Thrombopoietin
Thrombopoietin Signaling in Disease Conditions
Congenital Amegakaryocytic Thrombocytopenia (Chapter 30)
Essential Thrombocythemia (Chapter 71)
Additional Cytokines Involved in Megakaryocytopoiesis
Therapeutic Cytokine Stimulation of Megakaryocytopoiesis
Transcriptional Control Of Megakaryocytopoiesis
GATA Family Transcription Factors
GATA1
Friend of GATA (ZFPM1)
X-Linked Dyserythropoietic Anemia and Thrombocytopenia Caused by GATA1 Mutations
X-Linked Thrombocytopenia and Thalassemia Caused by GATA1 Mutations
X-Linked Gray Platelet–Like Syndrome
GATA1 Mutations in Down Syndrome Transient Myeloproliferative Disorders and Acute Megakaryoblastic Leukemia
E26 Transformation Specific Family Transcription Factors
Fli-1
ETS-Related Gene
ETV6 (TEL)
Other Transcription Factors
RUNX1
NF-E2 p45
SCL (TAL1)
Gfi-1b
HOX-Related Genes
MECOM (MDS1-EVI1)
c-Myb
Hypoxia-Inducible Factor 1-Alpha
Micro Rnas In Megakaryocytopoiesis
Future Directions
Suggested References
References
30
Inherited Bone Marrow Failure Syndromes
Introduction
Inherited Bone Marrow Failure Syndrome With Multi-Lineage Cytopenias
Fanconi Anemia
Background
Epidemiology
Genetics
Pathophysiology
Fanconi Anemia Genes and DNA Damage Repair
Fanconi Anemia Genes, Cell Survival, and Balancing Oxidative Stress
Pathogenesis of Bone Marro

lgrsnf/Hoffman R., et al. Hematology.. basic principles and practice (8ed., Elsevier, 2023)(ISBN 9780323733885)(O)(2787s)_BH_.pdf

Ronald Hoffman, Benz, Edward J., Jr., Leslie E. Silberstein, Helen Heslop, Jeffrey Weitz, Sanford J. Shattil, Bruce Furie, Harvey J. Cohen

Mosby, Incorporated

United States, United States of America

Eighth edition, Philadelphia, PA, 2023

S.l, 2023

2024-02-05