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.
journal_name
Leukemiajournal_title
Leukemiaauthors
Eisenwort G,Sadovnik I,Schwaab J,Jawhar M,Keller A,Stefanzl G,Berger D,Blatt K,Hoermann G,Bilban M,Willmann M,Winding C,Sperr WR,Arock M,Rülicke T,Reiter A,Valent Pdoi
10.1038/s41375-019-0460-6subject
Has Abstractpub_date
2019-11-01 00:00:00pages
2673-2684issue
11eissn
0887-6924issn
1476-5551pii
10.1038/s41375-019-0460-6journal_volume
33pub_type
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