Commitment to the Megakaryocytic Lineage

The most primitive megakaryocytic precursors, the burst-forming units of megakaryocytes (BFU-MK), express CD34 and CD109170 and are resistant to 5-fluorouracil treatment, in contrast to the more differentiated still CD34+HLA-DR+ megakaryocyte colony-forming units (CFU-MK).235 Mpl, the product of the gene encoding the thrombopoietic receptor, and GPIIb (CD41) are first expressed in CD34+ precursor cells together with CD9, a member of the tetraspanin superfamily,236 with GPIIb (CD41) and CD9 being weakly expressed even on bipotent BFU-E/MK.231,232,236,237 The low expression of CD41 by some CFU-GEMM235 and the finding that CD34+CD41+ bone marrow cells contain not only megakaryocytic but also erythroid and myeloid progenitors232 support the concept that this antigen is present on a fraction of multipotent progenitors, as demonstrated in the avian hematopoietic system.238 This would explain the finding of CD41/CD61 on monocytic CD14+ cells239 and on metamyelocytes-myelocytes during the chronic phase of some patients with chronic myeloid leukemia and myelodysplasia (Paietta E, unpublished observation). Although CD9 is lost upon erythroid differentiation, its expression is upregulated with increasing megakaryocytic differentiation.236 The CD34+GPIIb/IIIa+ (CD41/CD61; integrin anbP3) bone marrow cells give rise to CD34-GPIIb/IIIa+ cells, with an inverse relationship between GPIIb/IIIa and CD34 expression.240 GPIIb-IIIa functions as the platelet receptor for fibrinogen and von Willebrand factor (vWF). Another vWF receptor, the GPIbaP-V-IX complex, which in contrast to GPIIb is very specific for platelets, appears later during megakaryocytopoiesis.241 In culture, dissociated expression of GPIb-IX (CD42bc/CD42a) and GPV (CD42d) can be observed.241 The CD34+GPIIb/GPI-IIa+ promegakaryoblast, a transitional stage between clonal progenitors and morphologically recognizable megakaryocytic cells, contains platelet peroxidase and immature a-granules and stains with antibodies to vWF and factor VIII.240,242 CD34 is lost from the polyploid megakaryoblast concomitantly with the appearance of the GPIb-V-IX complex (CD42), of mature a granules in the cytoplasm,240 and of CD36 (GPIV, GPIIIb), the platelet collagen and thrombospondin receptor.233 Although an early differentiation marker in erythropoiesis, CD36 is a late feature in megakaryopoiesis. Signal transduction via CD36 results in platelet activation. First evidence for megakaryocyte maturation is the formation of demarcation membranes preceding the appearance of a-granules.240 Alpha granules contain P-selectin (CD62P), also called PADGEM (platelet activation-dependent granule-external membrane protein) or GMP-140 (granule membrane protein-140),as well as GPIIa (CD31),242 also termed PECAM-1 (platelet-endothelial cell adhesion molecule), a member of the Ig gene superfamily.210 On appropriate activation, these adhesion molecules are mobilized to the external plasma membrane. The receptor for thrombopoietin, c-mpl, clearly appears on late megakaryocytic progenitors and persists until the platelet stage.243 Although CD41/CD61, CD42, and CD51 (a-chain of the vitronectin receptor noncovalently associated with CD61, the p3 chain of the vitronectin receptor), do not react with granulocytes or monocytes, CD31 is expressed by monocytes, neutrophils, and a subset of lymphocytes.210 Alpha granules also contain fibrinogen, thrombospondin, and TGF-p,244 and the dense granules are storage pools for serotonin, calcium, and dense granular membrane proteins.242 The lysosomal granules contain CD63, which is translocated to the surface membrane on thrombin stimulation, and the lysosomal-plasma membrane shuttling proteins (lamp-1 and lamp-2, CD107a, CD107b). Platelets lack protein synthesis, and proteins expressed on the membrane on activation are released from intracellular storage sites. Megakaryocytes and platelets have pronounced migratory and adhesive capabilities related to the variety of adhesion molecules expressed by these cells, as indicated above. GPIIb/IIIa, the major platelet integrin, is the receptor for RGD-containing glycoproteins such as fibrinogen, vWF, and fibronectin. Other integrins involved in platelet adhesion and aggregation are VLA-2 (CD49b/CD29), VLA-5 (CD49e/CD29), and VLA-6 (CD49f/CD29).62-64

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