Granulocytes differentiate from early progenitors in the BM in a process that takes 7 to 10 days. The cells progress through several identifiable maturation stages, during which they acquire the morphologic appearance and granule contents that characterize the mature granulocyte. The earliest identifiable granulocyte precursor is the myeloblast, a minimally granulated cell with scant cytoplasm and a prominent nucleolus (Fig.). Transition to the promyelocyte stage is associated with the acquisition of abundant primary granules. Primary granules are found in both granulocytes and monocytes and contain proteins necessary for intracellular killing of microbes. The transition to the myelocyte stage is associated with the acquisition of secondary or “specific” granules, which give the characteristic staining pattern that differentiates neutrophils from eosinophils and basophils.

Neutrophil precursors account for approximately half the cells in the BM of normal individuals, with a majority of these at the meta myelocyte stage and beyond. Promyelocytes and myelocytes represent the primary proliferative pool of granulocyte precursors in the BM. Beyond the myelocyte stage, cells mature as nondividing cells. Bands and segmented neutrophils constitute greater than 50% of the total granulocyte mass, primarily as a storage pool of mature cells in the BM. Only 5% of total neutrophils circulate in the periphery, of which 60% are marginated in the spleen and on vessel walls. Mature neutrophils circulate in the peripheral blood for 3 to 24 hours and then migrate to the tissues, where they survive for 2 to 3 days. Therefore the peripheral neutrophil count reflects approximately 2% of the total neutrophil cell mass during approximately 1% of the neutrophil lifespan.

Biochemical events that accompany these physical changes include the sequential acquisition of primary granules and their content proteins (including myeloperoxidase [MPO], lysozyme, neutrophil elastase [NE; encoded by the ELANE gene], defensins, myeloblastin ), secondary granules and their content proteins (lactoferrin [LF], neutrophil collagenase [matrix metalloproteinase (MMP) 9], neutrophil gelatinase [matrix metalloproteinase (MMP) 8], neutrophil gelatinase-associated lipocalin [NGAL], transcobalamin 1), and tertiary granules containing neutrophil gelatinase . The progressive gain of these phenotypic changes and granule acquisition is accompanied by a loss of proliferative potential. This carefully coordinated process is disrupted in acute myeloid leukemia (AML), in which a block in the myeloid maturation pathway usually results in the circulation of immature blasts in the peripheral blood.