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 undergoes the spatial and temporal chain of events during the development of this disease has not been identified. Here we describe a CD133(+) stem cell population that drives the pathogenesis of primary myelofibrosis. Patient-derived circulating CD133(+) but not CD34(+)CD133(-) cells, with a variable burden for JAK2 (V617F) 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 a prefibrotic state, bone marrow/splenic fibrosis and transition to acute myeloid leukemia. Leukemic cells arose from a subset of CD133(+) cells harboring EZH2 (D265H) but lacking a secondary JAK2 (V617F) 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 primary myelofibrosis in mice. These results reveal the importance of the CD133 antigen in deciphering the neoplastic clone in primary myelofibrosis and indicate a new therapeutic target for myeloproliferative neoplasms.
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, Greece itriviai@gmail.com.
Ioanna
I
Triviai
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany.
Thomas
T
Stübig
Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
Birte
B
Niebuhr
Institute of Pathology, Hannover Medical School, Germany.
Kais
K
Hussein
Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, Greece.
Asterios
A
Tsiftsoglou
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany.
Boris
B
Fehse
Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
Carol
C
Stocking
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany.
Nicolaus
N
Kröger
D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood*; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D010455:Peptides / Q000097:blood*; D055728:Primary Myelofibrosis / Q000097:blood* / Q000175:diagnosis*
D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse