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Cell Death

Core Apoptosis Pathways Apoptosis is a biochemically well-defined programmed cell death that is essential for normal development and cellular homeostasis; dysregulation of apoptosis is involved in several diseases. The classical morphological features of apoptosis include cell shrinkage, membrane blebbing, nuclear condensation, and deoxyribonucleic acid (DNA) fragmentation. The biochemical hallmarks of apoptosis include permeabilization of the outer mitochondrial membrane (MOMP), activation of caspases, and the externalization of…

Control of Cell Division

The Cell Division Cycle The mammalian cell cycle is divided into four phases: mitosis (M), deoxyribonucleic acid (DNA) synthesis (S), and the gap phases G1 and G2 ( Fig. 17.1 ). Mitosis is recognized when cells visibly undergo cell division and chromatin becomes condensed, sequentially progressing through prophase, metaphase, anaphase, and telophase. The G1 phase occurs immediately after mitosis has been completed and ends when DNA…

Current Biology of Stem Cell Homing and Mobilization: Dynamic Interactions Between Hematopoietic Stem and Progenitor Cells and Their Surrounding Bone Marrow Microenvironment

Introduction Hallmarks of hematopoietic stem and progenitor cell (HSPC) function include their dynamic metabolism, active bi-directional migration (bone marrow [BM] homing, egress, recruitment, and mobilization to the blood), durable multilineage BM and blood repopulation potential, self-renewal and chemotherapy resistance. Hematopoietic stem cells (HSCs) mainly reside in the BM, and their chemotherapy resistance requires their quiescence, adhesion, and metabolic interactions with bone-forming stromal cells. However, HSPCs are…

Cell Adhesion

Cell adhesion is essential for the development and maintenance of multicellular organisms. Cell-to-cell and cell-to-matrix adhesion provide a mechanism for intercellular communication and to define the three-dimensional architecture of organs. The regulated nature of cell adhesion is particularly evident in the hematopoietic system, where blood cells routinely make transitions between nonadherent and adherent phenotypes during differentiation, and in response to stimuli in the circulation or extravascular…

Hematopoietic Microenvironment

Evolution of the Niche Concept In 1868, Ernest Neumann first suggested that blood cells are being replenished throughout postnatal life, and this proposal led to the attempts to localize the place of hematopoiesis. His hypothesis that blood cell production takes place in the bone marrow (BM) was experimentally validated by selective lead shielding of limbs in irradiated animals almost a century later. Notably, these and other…

Stem Cell Model of Hematologic Diseases

Cell-Of-Origin Studies in Hematologic Malignancies One of the prevailing models of cancer development proposes that a cancer is initiated and maintained through the function of CSCs, which represent a rare population of cells within a cancer that have an indefinite proliferative potential and are ultimately responsible for the generation of the bulk of cancer cells. This so-called CSC hypothesis has been best studied in hematopoietic malignancies.…

Role of Chemokines in Leukocyte Trafficking

The mammalian immune system has evolved to mount multifaceted molecular and cellular microbicidal responses tailored and custom-adapted to eliminate an endless variety of infectious agents and, at the same time, remain tolerant to self-antigens. Accomplishing these tasks requires continuous tightly controlled movement of billions of motile immune cells that roam throughout the body along distinct nonrandom traffic routes from one tissue to another using blood and…

Cytokines, Chemokines, Other Growth Factors, and Their Receptors

Introduction Hematopoiesis is regulated by cytokine-cell and cell-cell interactions. Cytokines are polypeptides secreted by many cell types either constitutively or after induction and are usually classified based on primary structures associated with their receptor extracellular domains. They regulate a large range of biologic functions, including hematopoiesis, immunity, and inflammation. In context of hematopoiesis, they have effects on proliferation, differentiation, survival/cell death (apoptosis), and cell movement/migration/induced mobilization.…

Mitochondria and Hematopoiesis

Mitochondrial Structure and Function Mitochondria are very complex and highly dynamic organelles. Although responsible for only 10% of the cellular proteome, mitochondria serve not only as powerhouse of the cells but also as critical regulators of essential cellular processes including iron-sulfur cluster biosynthesis, calcium homeostasis, and cell death; hence they contribute to health and disease. Mitochondria are surrounded by a double-membrane system, consisting of an inner…

Hematopoietic Stem Cell Biology

Hematopoietic stem cells (HSCs) are characterized by their unique ability to self-renew and give rise to the entirety of the blood and immune system throughout the lifetime of an individual. HSCs are very rare cells, representing approximately one in 100,000 bone marrow (BM) cells in the adult. The concept of the existence of an HSC that is capable of reconstituting hematopoiesis in vivo was first introduced…

Pharmacogenomics and Hematologic Diseases

It is widely recognized that heritable genetic variation (i.e., genotypes or haplotypes) can translate into inherited phenotypes, some of which predispose to or cause diseases and others alter response to treatment. One aim of medical genetics and pharmacogenomics (PGx) is to understand the myriad associations between inherited genotypes and specific phenotypes of disease or drug response, with the ultimate goal of better defining the risk for,…

Protein Architecture: Relationship of Form and Function

Previous chapters outline the central dogma of mlecular biology: the storage of genetic information in DNA and its regulated transcription into messenger RNA and eventual translation into proteins. In this chapter, we briefly outline the chemical structure of proteins and their posttranslational modifications (PTMs). We explain how the properties of the 20 amino acids of which proteins are composed allow these polymers to fold into compact,…

Signaling Transduction and Metabolomics

Hematopoiesis is a cellular process in which self-renewing stem progenitor cells differentiate into mature blood cells, which carry out specific biologic functions. These functions include oxygen delivery, clot formation, and immune responses, including defense of the host from infection and inflammation. Homeostasis of the whole hematopoietic system in vivo requires a tight control of systems and networks governing proliferation, cell fate, cell death, differentiation, cell–cell interaction,…

Genome Editing

Genome editing is a rapidly developing field in which the genome of cells is modified with single nucleotide precision. This degree of precision is not achievable by other forms of genetic engineering, including contemporary lentiviral vectors, recombinases, or transposases. Not only is genome editing precise in the location of the changes made, but it is highly flexible and robust in the types of changes that can…

Regulation of Gene Expression in Hematology

Introduction The function of a cell is not only determined by the sum of the specific RNAs and proteins expressed but also by their metabolism, modification, and localization. To understand how a cell behaves, one must understand how the expression of genes, translation of transcripts, and processing of proteins are regulated. Through concerted regulation of these processes, hematopoietic stem cells (HSCs) maintain a balance between quiescence…

Genomic Approaches to Hematology

Introduction The publication of the sequence of the human genome in 2001 heralded a new era in biomedical research and delivered a novel perspective on the biologic basis of the leukemias and lymphomas. A major tenet of these new approaches was their emphasis on the generation of large unbiased datasets as a means of discovery. The rapid application of this methodology combined with ready access to…

Epigenomics in Hematology

Epigenetics can be defined as inheritance of variation, above and beyond changes in the DNA sequence. In other words, epigenetics comprises the study of how cells sharing the same exhaustive DNA blueprint can appear and function so distinctly as white blood cells, hepatocytes, neurons, etc. Whereas the genome contains all of the vital information to direct the development of an organism, the epigenome dynamically filters and…

Anatomy and Physiology of the Gene

Normal blood cells have limited life spans; they must be replenished in precise numbers by a continuously renewing population of progenitor cells. Homeostasis of the blood requires that proliferation of these cells be efficient yet strictly constrained. Many distinctive types of mature blood cells must arise from these progenitors by a controlled process of commitment to, and execution of, complex programs of differentiation. Thus developing red…

Appendix

Chapter Outline Preparation of commonly used reagents 561 Water 561 Anticoagulants and preservative solutions 561 Buffers 562 Preparation of glassware 564 Cleaning slides 564 Cleaning glassware 564 Sizes of tubes 565 Speed of centrifugation 565 Statistical procedures 565 Calculations 566 Analysis of differences by t -test 566 Analysis of variation by F -ratio 566 Automated (mechanical) pipettes 567 Autodiluters 567 Preparation of commonly used reagents Water…

Haematology in Under-Resourced Laboratories

Introduction: types of laboratories In most countries, there are likely to be some laboratories with limited resources, but in under-resourced countries, the majority of laboratories face chronic shortages of trained staff, low morale, inadequate and poorly maintained equipment and erratic supplies of reagents and essential supplies. These factors have a major impact on the range and quality of services offered. Many laboratories lack the highly sophisticated…