granulopoiesis

**Pathway (bone marrow):** Hematopoietic stem cell (HSC) → common myeloid progenitor (CMP) → granulocyte-monocyte progenitor (GMP) → myeloblast → promyelocyte (primary/azurophilic granules, contain myeloperoxidase) → myelocyte (secondary/specific granules appear; lineage commitment to neutrophil, eosinophil, or basophil) → metamyelocyte → band (stab) cell → mature segmented granulocyte. Maturation takes about 7–10 days, and the cells are then stored in a marrow reserve pool. Neutrophils then circulate for only about 6–10 hours before entering tissues.

**Regulators:** - IL-3 and GM-CSF: early multipotent and myeloid progenitor expansion. - G-CSF: neutrophil lineage proliferation, differentiation, and release from marrow. Receptor signals via JAK2/STAT3. Transcription factors include PU.1 and C/EBPα (needed for the myeloid fate and the myeloblast-to-promyelocyte transition) and C/EBPε (needed for secondary granule formation). - IL-5: eosinophils. - IL-3 and GM-CSF (and stem cell factor): basophils and mast cell lineage support. - Sources of the cytokines include stromal cells, macrophages, endothelium, and T cells, especially during infection.

**Pools:** Marrow storage pool is the largest. Circulating and marginated pools are in equilibrium, and demargination occurs with stress, epinephrine, or glucocorticoids. This causes leukocytosis without increased production.

**Clinical correlations:** - **Left shift:** Increased bands and immature forms in the blood occur in infection or inflammation, reflecting accelerated granulopoiesis and early release. - **Leukemoid reaction vs CML:** A leukemoid reaction has a high leukocyte alkaline phosphatase (LAP) score. CML has a low LAP score, t(9;22) BCR-ABL, basophilia, and a full spectrum of myeloid maturation. - **Acute promyelocytic leukemia (AML M3):** Maturation arrest at the promyelocyte stage. It is associated with t(15;17) PML-RARα, Auer rods, and DIC. Treatment is ATRA (all-trans retinoic acid), which induces differentiation, plus arsenic trioxide. - **Neutropenia:** Causes include severe congenital neutropenia (Kostmann syndrome; ELANE or HAX1 mutations, maturation arrest at the promyelocyte stage), cyclic neutropenia (ELANE mutation, ~21-day cycles), drug-induced (clozapine, carbamazepine, PTU, chemotherapy), and aplastic anemia or marrow infiltration. An ANC <500/µL puts the patient at high risk for infection. - **Pharmacology:** Filgrastim (G-CSF) and pegfilgrastim are used for chemotherapy-induced neutropenia and to mobilize stem cells. Sargramostim (GM-CSF) is used after bone marrow transplant. Adverse effects include bone pain and splenic rupture (rare, but it comes up on exams, along with leukocytosis). - **Eosinophilia:** Driven by IL-5 in allergy, parasitic infections (helminths), and drug reactions (DRESS). Mepolizumab (anti-IL-5) is used for eosinophilic asthma. - **Pelger-Huët anomaly:** Lamin B receptor defect causes bilobed neutrophils with normal function. Chediak-Higashi syndrome (LYST) causes giant granules.

**High-yield contrasts:** Granulopoiesis (G-CSF) is distinct from erythropoiesis (erythropoietin from peritubular interstitial cells in the kidney) and from thrombopoiesis (thrombopoietin from the liver). Monocytes arise from the same GMP but are driven by M-CSF.