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C H A P T E R 27

GRANULOCYTOPOIESIS AND MONOCYTOPOIESIS

Arati Khanna-Gupta and Nancy Berliner

GRANULOCYTOPOIESIS progressive gain of these characteristics is accompanied by a loss of
proliferative potential. This carefully coordinated process is disrupted
Granulocytes (neutrophils, eosinophils, and basophils) are short- in acute myeloid leukemias (AMLs), in which a block in the myeloid
lived cells that are critical to both antimicrobial and inflammatory maturation pathway usually results in the circulation of immature
responses. The bone marrow (BM) produces granulocytes, especially blasts in the peripheral blood.
neutrophils, at a prodigious rate to supply the baseline needs of cir-
culating cells that survive in the peripheral blood only 3 to 24 hours.
It also has the capacity to increase granulocyte production sharply in Markers of Granulocytic Maturation
response to a wide range of stresses. The regulation of granulocyte
production is controlled by a variety of cytokines that induce the Stem cells have been characterized primarily by their marrow
myeloid differentiation program through the carefully orchestrated repopulating potential, as outlined in Chapter 10. Early granulocytic
interaction of multiple general and myeloid-specific transcription progenitors form hematopoietic colonies in vitro, and their more
factors. Understanding this intricate maturation sequence provides differentiated progeny express specific cell surface proteins that are
important insights into normal neutrophil responses to infectious, critically important to myeloid differentiation and function. They
inflammatory, and allergic stresses, as well as into the dysregulation mediate both the adhesion of precursors within the BM and the
of differentiation contributing to myelodysplasia and leukemia. vascular adhesion of mature neutrophils that is critical to normal
neutrophil activation. Other proteins serve as receptors that recognize
Granulocyte Ontogeny pathogens or as stimulatory peptides that facilitate activation of
phagocytosis and killing of organisms. Appropriate expression of
these surface proteins plays an important role in normal neutrophil
Stages of Neutrophil Differentiation function, and abnormalities of their expression are implicated in
a wide range of diseases affecting the neutrophil compartment.
Granulocytes differentiate from early progenitors in the BM in For example, congenital abnormalities in the surface expression of
a process that takes 7 to 10 days. The cells pass through several integrin proteins are responsible for failure of neutrophil adhesion
identifiable maturational stages, during which they acquire the in leukocyte adhesion deficiency, whereas acquired abnormalities of
morphologic appearance and granule contents that characterize the expression of the same proteins are hypothesized to underlie the
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mature granulocyte. The earliest identifiable granulocyte precursor is abnormal circulation of immature precursors in myeloproliferative
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the myeloblast, a minimally granulated cell with scant cytoplasm and neoplasms. These markers also serve to help distinguish among the
a prominent nucleolus (Fig. 27.1). Transition to the promyelocyte stages of myeloid commitment and maturation.
+
stage is associated with the acquisition of abundant primary granules. The phenotype of the early hematopoietic stem cells is CD34 /
-
Primary granules are found in both granulocytes and monocytes and CD33 , with absence of lineage-specific markers. The common
contain many of the proteins necessary for intracellular killing of myeloid progenitor, colony-forming unit–granulocyte–erythrocyte–
microbes. The transition to the myelocyte stage is associated with macrophage–megakaryocyte (CFU-GEMM), is characterized by
the acquisition of secondary or “specific” granules, which give the the coexpression of CD33. CD33 is expressed at high levels on
characteristic staining pattern that differentiates neutrophils from committed myeloid progenitors and on early precursors of both the
eosinophils and basophils. granulocytic and monocytic lineages. Expression of CD33 wanes with
Neutrophil precursors account for approximately half of the cells granulocytic maturation, and it is absent or nearly absent beyond the
in the BM of normal individuals, with a majority of these at the myelocyte stage. CD33 is a member of the sialic acid–binding Ig-like
metamyelocyte stage and beyond. Promyelocytes and myelocytes lectins (siglecs), which generally mediate cell–cell interactions and cell
represent the primary proliferative pool of granulocyte precursors signaling. The precise biologic function of CD33 itself is unknown.
in the BM. Beyond the myelocyte stage, cells mature as nondivid- Characteristic granulocyte markers acquired as the early myeloid
ing cells. Bands and segmented neutrophils constitute greater than progenitor cells become committed to the neutrophil lineage include
50% of the total granulocyte mass, primarily as a storage pool of CD45RA, myeloperoxidase (MPO), and CD38, all of which are
mature cells in the BM. Only 5% of total neutrophils circulate in expressed on the myeloblast. Further differentiation beyond the
the periphery, where 60% are marginated in the spleen and on vessel myelocyte stage is associated with acquisition of increased expression
walls. Mature neutrophils circulate in the peripheral blood for 3 to of CD16, CD11b/CD18 (Mac-1), and leukocyte alkaline phos-
24 hours and then migrate to the tissues, where they survive 2 to phatase (LAP), all of which are expressed at high levels in mature
3 days. Hence the peripheral neutrophil count reflects roughly 2% neutrophils.
of the total neutrophil cell mass during approximately 1% of the
neutrophil life span.
Biochemical events that accompany these physical changes Neutrophil Granules and Their Content Proteins
include the sequential acquisition of primary granules and their
content proteins (e.g., myeloperoxidase, lysozyme, neutrophil elastase The acquisition of granules and their content proteins is a critical
3
[NE, also known as ELANE], defensins, myeloblastin), secondary part of the developmental program of the granulocyte. Acquired at
granules and their content proteins (lactoferrin [LF], neutrophil specific identifiable stages of neutrophil maturation, these intracel-
collagenase (MMP8), neutrophil gelatinase [MMP9], neutrophil lular and secretory organelles contain many of the requisite enzymes
gelatinase-associated lipocalin [NGAL], transcobalamin 1), and that mediate the oxidative and nonoxidative killing functions of the
tertiary granules containing neutrophil gelatinase (Table 27.1). The neutrophil (see Table 27.1).

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