HSC behavior in PV. (A) HSC physiology. Current concepts of the HSC hierarchy.¹³  At the apex of the HSC hierarchy is the long-term HSC (LT-HSC; CD34⁺CD38⁻ cell), which is responsible for lifetime maintenance of bone marrow cellular integrity and in which all MPN driver mutations are expressed. In addition to the classical commitment pathway through the short-term HSC (ST-HSC), LT-HSCs can give rise directly to committed, self-repopulating HSCs restricted to megakaryocytopoiesis (MkRP), megakaryocytopoiesis and erythropoiesis (MERP), or all myeloid cells (common myeloid–repopulating [CMRP]). Importantly, the thrombopoietin receptor, MPL, is the only hematopoietic growth factor receptor expressed in LT-HSCs because, in addition to its effects as an HSC growth factor, it is responsible for tethering LT-HSCs in their marrow niches to osteoblast-expressed thrombopoietin (THPO). LT-HSCs are largely dormant, insensitive to MPN driver mutations; expansion of the MPN LT-HSC population at the expense of normal LT-HSCs can take years to occur. At the base of the hierarchy are the committed hematopoietic progenitor cells, which are hyperproliferative, addicted to MPN driver mutations, and sensitive to JAK1/2 inhibitors. (B) Conversion to PV in an ET patient 6 years after diagnosis associated with the development of JAK2^V617F homozygosity, a PV hallmark. (C) Conversion to PV in a PMF patient after 17 years. The bar indicates hydroxyurea therapy. EPO-R, erythropoietin receptor; ery, erythroid progenitor; G-CSFR, granulocyte colony-stimulating factor receptor; LMPP, lymphoid-primed multipotent progenitor; meg, megakaryocyte; MP, myeloid progenitor; MyRP, myeloid-restricted repopulating progenitor; n/m, neutrophil/monocyte progenitor.