Myeloproliferative neoplasms are clonal proliferations of bone marrow stem cells, which can manifest as an increased number of platelets, red blood cells (RBCs), or white blood cells (WBCs) in the circulation and sometimes as increased fibrosis in the bone marrow with consequent extramedullary hematopoiesis (cell production outside the marrow). Based on these abnormalities, they are classified as
Essential thrombocythemia, primary myelofibrosis, and polycythemia vera are Philadelphia chromosome–negative myeloproliferative neoplasms that can spontaneously transform to acute leukemia. Essential thrombocythemia and polycythemia vera transform at very low rates in the absence of prolonged exposure to chemotherapeutic agents.
Each disorder is identified according to its predominant features (see table Classification of Myeloproliferative Neoplasms). Overlap in of clinical and laboratory findings occurs because essential thrombocythemia. primary myelofibrosis, and polycythemia vera can have driver mutations that constitutively activate Janus kinase 2 (JAK2). Although proliferation of one or more hematopoietic cell types dominates the clinical picture in each of these disorders, all three are caused by clonal proliferation of a pluripotent hematopoietic stem cell, causing an increased proliferation of normal RBC, WBC, and platelet progenitors in the bone marrow. This abnormal clone does not, however, produce bone marrow fibroblasts, which can proliferate in a polyclonal reactive fashion in response to the abnormal stem cell.
Mutations of the Janus kinase 2 (JAK2) gene are responsible for polycythemia vera and a high proportion of cases of essential thrombocythemia and primary myelofibrosis. Janus kinase 2 is a member of the tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF) among other entities. The thrombopoietin receptor gene (MPL) or the calreticulin (CALR) gene is also mutated in a significant proportion of essential thrombocythemia and primary myelofibrosis patients and rarely in polycythemia vera.