Since MPL is essential to maintain HSC quiescence and survival in the marrow osteoblastic niche [17,18,55], while it is also responsible for THPO catabolism [54], we postulated that impaired MPL expression was central to MPN phenotypic behavior, causing myeloproliferation by HPC and eventually myelofibrosis due to increased circulating THPO, depending on the MPN driver mutation allele burden, while paradoxically permitting loss of HSC from marrow. The gene discussed is THPO; the disease is myelofibrosis.