Advances in polycythemia vera and lessons for acute leukemia

The myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocytosis and primary myelofibrosis, are an unusual group of myeloid neoplasms, which arise in a pluripotent hematopoietic stem cell (HSC) due to gain of function driver mutations in the JAK2, CALR and MPL genes that constitutively activate JAK2, the cognate tyrosine kinase of the type 1 hematopoietic growth factor (HGF) receptors. PV is the ultimate phenotypic expression of constitutive JAK2 activation since it alone of the three MPN is characterized by overproduction of normal red cells, white cells and platelets. Paradoxically, however, although PV is a panmyelopathy involving myeloid, erythroid and megakaryocytic progenitor cells, pluripotent HSC only express a single type of HGF receptor, the thrombopoietin receptor, MPL. In this review, the basis for how a pluripotent HSC with one type of HGF can give rise to three separate types of myeloid cells will be explained and it will be demonstrated that PV is actually a hormone-sensitive disorder, characterized by elevated thrombopoietin levels. Finally, it will be shown that the most common form of acute leukemia in PV is due to the inappropriate use of chemotherapy, including hydroxyurea, which facilitates expansion of DNA-damaged, mutated HSC at the expense of their normal counterparts.