Abstract
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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Acknowledgements
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.
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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.
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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.
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Eisenwort, G., Sadovnik, I., Schwaab, J. et al. Identification of a leukemia-initiating stem cell in human mast cell leukemia. Leukemia 33, 2673–2684 (2019). https://doi.org/10.1038/s41375-019-0460-6
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DOI: https://doi.org/10.1038/s41375-019-0460-6
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