CD133 marks a stem cell population that drives human Primary Myelofibrosis

Primary Myelofibrosis is a Myeloproliferative Neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, extramedullary hematopoiesis, and transformation to Acute Myeloid Leukemia. To date the stem cell that incurs the spatial and temporal chain of events during disease development has not been identified. Here we report a CD133+ stem cell population that drives Primary Myelofibrosis pathogenesis. Patient-derived circulating CD133+ but not CD34+CD133- cells, with variable burden for JAK2V617F mutation, had multipotent cloning capacity in vitro. CD133+ cells engrafted for up to 10 months in immunocompromised mice and differentiated into JAK2-V617F+ myeloid but not lymphoid progenitors. We observed the persistence of human, atypical JAK2-V617F+ megakaryocytes, the initiation of prefibrotic state, bone marrow/splenic fibrosis and transition to Acute Myeloid Leukemia. Leukemic cells arose from a subset of CD133+ cells harboring EZH2D265H but lacking secondary JAK2V617F mutation, consistent with the hypothesis that deregulation of EZH2 activity drives clonal growth and increases the risk of Acute Myeloid Leukemia. This is the first characterization of a patient-derived stem cell population that drives disease resembling both chronic and acute phases of PMF in mice. These results reveal the importance of the CD133 antigen in deciphering the neoplastic clone in Primary Myelofibrosis and introduce a new therapeutic target for Myeloproliferative Neoplasms.