THPO and myelofibrosis: Because MPL is essential for HSC quiescence and survival in the marrow osteoblastic niche (22, 23, 67) and is also responsible for THPO catabolism (57), we hypothesized that impaired MPL cell-surface expression was essential for MPN phenotypic behavior, causing unregulated HPC proliferation and, eventually, myelofibrosis due to increased plasma THPO (30), depending on the MPN driver mutation allele burden, while also causing HSC loss from the marrow (22).