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

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 LSC in all cases, as well as the D816V mutant form of KIT. Whereas 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.

Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis

“…48 More recently, leukemic stem cells for MCL have been reported to reside in the CD34 + /CD38fraction of the malignant clone. 49 In light of these reports our iPSC-based SM disease model stands as a powerful tool for the systematic evaluation of KIT D816V impact on the different stages of hematopoiesis.…”

Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future

“…Such MCL-initiating stem cells have recently been identified in advanced SM (98). One effective approach to kill such quiescent (stem) cells may be to apply antibody-based toxin conjugates or other targeted antibodies (63,99,100). The CD30 antibody-based drug brentuximab-vedotin has recently been considered for the treatment of patients with advanced SM (63) and a clinical trial in patients with CD30+ ASM and MCL has recently been initiated in the USA.…”

Redistribution, homing and organ-invasion of neoplastic stem cells in myeloid neoplasms

“…So far, little is known about the phenotype of long-term disease-propagating NSC/LSC in myeloid neoplasms. In most myeloid malignancies, these cells are considered to reside within a CD34 + sub-fraction of the malignant clone, based on their in vivo long-term disease-propagating capacity [32][33][34][35][36][37][38][39][40][41][42]. In chronic myeloid neoplasms where neoplastic cells retain a substantial differentiation and maturation potential, like in CML, low risk MDS, or advanced SM, the disease-initiating and -propagating cells are detected preferentially in a CD34 + /CD38 − subpopulation, thereby resembling the basic phenotype of normal hematopoietic stem cells [41][42][43][44].…”

“…In most myeloid malignancies, these cells are considered to reside within a CD34 + sub-fraction of the malignant clone, based on their in vivo long-term disease-propagating capacity [32][33][34][35][36][37][38][39][40][41][42]. In chronic myeloid neoplasms where neoplastic cells retain a substantial differentiation and maturation potential, like in CML, low risk MDS, or advanced SM, the disease-initiating and -propagating cells are detected preferentially in a CD34 + /CD38 − subpopulation, thereby resembling the basic phenotype of normal hematopoietic stem cells [41][42][43][44]. However, in high risk MDS, AML, and in the blast phase of CML, the disease-initiating and propagating stem cells may also reside in a CD34 + / CD38 + cell compartment [41,45,46].…”