Mast cell leukemia (MCL) is a highly fatal malignancy characterized by devastating expansion of immature mast cells in various organs. Although considered a stem cell disease, little is known about MCL-propagating neoplastic stem cells. We here describe that leukemic stem cells (LSCs) in MCL reside within a CD34+/CD38 fraction of the clone. Whereas highly purified CD34+/CD38 cells engrafted NSGhSCF mice with fully manifesting MCL, no MCL was produced by CD34+/CD38+ progenitors or the bulk of KIT+/CD34 mast cells. CD34+/CD38 MCL cells invariably expressed CD13 and CD133, and often also IL-1RAP, but did not express CD25, CD26 or CLL-1. CD34+/CD38 MCL cells also displayed several surface targets, including CD33, which was homogenously expressed on MCL LSCs in all cases, and the D816V mutant form of KIT. Although CD34+/CD38 cells were resistant against single drugs, exposure to combinations of CD33-targeting and KIT-targeting drugs resulted in LSC-depletion and markedly reduced engraftment in NSGhSCF mice. Together, MCL LSCs are CD34+/CD38 cells that express distinct profiles of markers and target antigens. Characterization of MCL LSCs should facilitate their purification and should support the development of LSC-eradicating curative treatment approaches in this fatal type of leukemia.

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We would like to thank Tina Bernthaler, Mathias Schneeweiss, Karin Bauer, Niklas Müller and Sabine Cerny-Reiterer for skillful technical assistance. This study was supported by the Austrian Science Fund (FWF), SFB grants F4701 and F4704, and a Research Grant of the Medical University of Vienna, Austria. Cell-sorting experiments were performed with support from the Core Facility Flow Cytometry, Medical University of Vienna.

Author information


  1. Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090, Vienna, Austria

    • Gregor Eisenwort
    • , Irina Sadovnik
    • , Katharina Blatt
    • , Michael Willmann
    • , Wolfgang R. Sperr
    • , Thomas Rülicke
    •  & Peter Valent
  2. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090, Vienna, Austria

    • Gregor Eisenwort
    • , Irina Sadovnik
    • , Alexandra Keller
    • , Gabriele Stefanzl
    • , Daniela Berger
    • , Katharina Blatt
    • , Wolfgang R. Sperr
    •  & Peter Valent
  3. Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, 68167, Mannheim, Germany

    • Juliana Schwaab
    • , Mohamad Jawhar
    •  & Andreas Reiter
  4. Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria

    • Gregor Hoermann
    •  & Martin Bilban
  5. Department for Companion Animals & Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, 1210, Vienna, Austria

    • Michael Willmann
  6. Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, 1210, Vienna, Austria

    • Christiana Winding
    •  & Thomas Rülicke
  7. Cellular and Molecular Oncology, LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, 94230, Cachan, France

    • Michel Arock


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GE and PV planned the study; GE, IS, AK, DB, KB, GS and CW performed the experiments; GE, GH, MB, MW, TR, and PV analyzed the data; JS, MJ, MW, WRS, TR, AR, MA and PV provided research materials; GE, GH, MW, MA, AR and PV wrote the manuscript.

Conflict of interest

PV received a research grant from Novartis, from Blueprint, and from Deciphera, and received honoraria from Novartis, Celgene, Pfizer and Deciphera. PV and AR served as a Consultant in the global Novartis trial examining the effects of midostaurin in advanced SM. WRS received honoraria from Novartis and Celgene. MA received honoraria from Deciphera, Novartis and Roche Diagnostics, and a research grant from Agensys Inc., Blueprint Medicines and Deciphera. AR received a research grant from Novartis, honoraria from Novartis and BMS, and served in advisory boards organized by Deciphera, Blueprint and Baxalta/Shire. GH received honoraria from Novartis. The other authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Peter Valent.

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