Ivanov, Daniel (Medical University of Vienna) Daniel Ivanov Valent, Peter (Medical University of Vienna) Peter Valent Sliwa, Thamer (Hanusch Hospital) Thamer Sliwa Fillitz, Michael (Hanusch Hospital) Michael Fillitz Eisenwort, Gregor (Medical University of Vienna) Gregor Eisenwort Machherndl-Spandl, Sigrid (Johannes Kepler University of Linz / Krankenhaus der Elisabethinen) Sigrid Machherndl-Spandl Hoermann, Gregor (Medical University of Vienna / Munich Leukemia Laboratory) Gregor Hoermann Dahlhoff, Maik (University of Veterinary Medicine Vienna / Medical University of Vienna / University of Vienna / Center for Biomarker Research in Medicine) Maik Dahlhoff Rülicke, Thomas (University of Veterinary Medicine Vienna / Medical University of Vienna) Thomas Rülicke Hadzijusufovic, Emir (Medical University of Vienna) Emir Hadzijusufovic Slavnitsch, Katharina (University of Veterinary Medicine Vienna / Medical University of Vienna) Katharina Slavnitsch Greiner, Georg (Medical University of Vienna / Ihr labor) Georg Greiner Kralovics, Robert (Medical University of Vienna) Robert Kralovics Willmann, Michael (University of Veterinary Medicine Vienna / Medical University of Vienna) Michael Willmann Peter, Barbara (Medical University of Vienna) Barbara Peter Herrmann, Harald (Medical University of Vienna) Harald Herrmann Sadovnik, Irina (Medical University of Vienna) Irina Sadovnik Milosevic Feenstra, Jelena D. (Medical University of Vienna) Jelena D. Milosevic Feenstra Keil, Felix (Medical University of Vienna / Hanusch Hospital) Felix Keil Gisslinger, Heinz (Medical University of Vienna) Heinz Gisslinger Pfeilstöcker, Michael (Medical University of Vienna / Hanusch Hospital) Michael Pfeilstöcker Koller, Elisabeth (Hanusch Hospital) Elisabeth Koller Speer, Wolfgang R. (Medical University of Vienna) Wolfgang R. Speer Bettelheim, Peter (Krankenhaus der Elisabethinen) Peter Bettelheim Krauth, Maria-Theresa (Medical University of Vienna) Maria-Theresa Krauth Wiley 2023 Myeloproliferative neoplasms (MPN) are characterized by uncontrolled expansion of myeloid cells, disease-related mutations in certain driver-genes including JAK2, CALR, and MPL, and a substantial risk to progress to secondary acute myeloid leukemia (sAML). Although behaving as stem cell neoplasms, little is known about disease-initiating stem cells in MPN. We established the phenotype of putative CD34+ /CD38- stem cells and CD34+ /CD38+ progenitor cells in MPN. A total of 111 patients with MPN suffering from polycythemia vera, essential thrombocythemia, or primary myelofibrosis (PMF) were examined. In almost all patients tested, CD34+ /CD38- stem cells expressed CD33, CD44, CD47, CD52, CD97, CD99, CD105, CD117, CD123, CD133, CD184, CD243, and CD274 (PD-L1). In patients with PMF, MPN stem cells often expressed CD25 and sometimes also CD26 in an aberrant manner. MPN stem cells did not exhibit substantial amounts of CD90, CD273 (PD-L2), CD279 (PD-1), CD366 (TIM-3), CD371 (CLL-1), or IL-1RAP. The phenotype of CD34+ /CD38- stem cells did not change profoundly during progression to sAML. The disease-initiating capacity of putative MPN stem cells was confirmed in NSGS mice. Whereas CD34+ /CD38- MPN cells engrafted in NSGS mice, no substantial engraftment was produced by CD34+ /CD38+ or CD34- cells. The JAK2-targeting drug fedratinib and the BRD4 degrader dBET6 induced apoptosis and suppressed proliferation in MPN stem cells. Together, MPN stem cells display a unique phenotype, including cytokine receptors, immune checkpoint molecules, and other clinically relevant target antigens. Phenotypic characterization of neoplastic stem cells in MPN and sAML should facilitate their enrichment and the development of stem cell-eradicating (curative) therapies. PDFDocument en 2024-08-12T07:53:21.871Z Acute Myeloid-Leukemia; Polycythemia-Vera; Hematopoietic Stem; Progenitor Cells; Myelofibrosis; Transplantation; Expression; Target; Mice; Discoveries 4271012 b application/pdf CC BY 4.0 International