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Leukemia. 2019 Apr 5. doi: 10.1038/s41375-019-0460-6. [Epub ahead of print]

Identification of a leukemia-initiating stem cell in human mast cell leukemia.

Author information

1
Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090, Vienna, Austria.
2
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090, Vienna, Austria.
3
Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, 68167, Mannheim, Germany.
4
Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria.
5
Department for Companion Animals & Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.
6
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.
7
Cellular and Molecular Oncology, LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, 94230, Cachan, France.
8
Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090, Vienna, Austria. peter.valent@meduniwien.ac.at.
9
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090, Vienna, Austria. peter.valent@meduniwien.ac.at.

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.

PMID:
30953030
DOI:
10.1038/s41375-019-0460-6

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