Thrombocytosis.
Major progress in understanding the pathogenesis in patients with thrombocytosis has been made by identifying mutations in the key regulators of thrombopoietin: the thrombopoietin receptor MPL and JAK2. Together, these mutations can be found in 50% to 60% of patients with essential thrombocythemia or primary myelofibrosis and in 10% to 20% of hereditary thrombocytosis. A decrease in expression of the Mpl protein can cause thrombocytosis even in the absence of mutations in the coding sequence, due to a shift in the balance between stimulation of signaling in megakaryopoiesis and removal of thrombopoietin by receptor mediated internalization in platelets. When present in a heterozygous state the JAK2-V617F mutation preferentially stimulates megakaryopoiesis and in most cases manifests as essential thrombocythemia (ET), whereas homozygous JAK2-V617F reduces megakaryopoiesis in favor of increased erythropoiesis, resulting in polycythemia vera and/or myelofibrosis. In 30% to 40% of patients with ET or primary myelofibrosis (PMF) and in 80% to 90% of pedigrees with hereditary thrombocytosis the disease-causing gene remains unknown. Ongoing genetic and genomic screens have identified genes that, when mutated, can cause thrombocytosis in mouse models. A more complete picture of the pathways that regulate megakaryopoisis and platelet production will be important for finding new ways of controlling platelet production in patients with thrombocytosis.
Skoda
Radek C
RC
Experimental Hematology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland. radek.skoda@unibas.ch
D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D020125:Mutation, Missense; D011087:Polycythemia Vera / Q000235:genetics; D055728:Primary Myelofibrosis / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050791:STAT Transcription Factors / Q000502:physiology; D013920:Thrombocythemia, Essential / Q000235:genetics; D013922:Thrombocytosis / Q000235:genetics*; D034061:Thrombopoiesis / Q000235:genetics; D013926:Thrombopoietin / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D014161:Transduction, Genetic
C481270:Mpl protein, mouse; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D050791:STAT Transcription Factors; C082218:MPL protein, human; D013926:Thrombopoietin; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2