title: Stochastic acquisition of a stem cell-like state and drug tolerance in leukemia cells stressed by radiation.
abstract: A rare population of leukemia cells have the properties of leukemia stem cells (LSCs) and cause resistance to therapy, but their development is not clearly understood. In the current study, we show that a higher resistance to cytotoxic drug (Ara-C) can be developed in the subpopulation of promyelocytic leukemia cells that survived radiation treatment. These drug-tolerant leukemia cells (DTLs) are not observed immediately after radiation despite extensive genetic instability in the cells, but appear in 3 weeks of recovery culture. Moreover, when the single cell-derived clones were examined by clonal trafficking, no correlation between radio-resistant and chemo-resistant leukemic clones was detected, indicating that the resistance is developed by active acquisition of the resistance without clonal predisposition. Interestingly, the DTLs mimicked the characteristics of LSCs exhibiting leukemia-initiating activities and lower levels of reactive oxygen species or a higher level expression of bmi-1 as well as higher resistance to retinoic acid-induced differentiation compared to parental leukemic cells. These studies show that an active reacquisition of stem cell-like properties can occur in the leukemia cells to develop resistance to treatments and that such reacquisition process of leukemic cells occurs in a stochastic manner triggered by radiation stress on leukemic cells.
authors.affiliation: Catholic High-Performance Cell Therapy Center, College of Medicine, The Catholic University of Korea, 505, Banpo-Dong, Seocho-Ku, Seoul 137-701, Republic of Korea.
authors.forename: Ga-Young
authors.initials: GY
authors.lastname: Lee
authors.forename: Jae-Seung
authors.initials: JS
authors.lastname: Shim
authors.forename: Bin
authors.initials: B
authors.lastname: Cho
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Jung
authors.forename: Dong-Soon
authors.initials: DS
authors.lastname: Lee
authors.forename: Il-Hoan
authors.initials: IH
authors.lastname: Oh
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005720:Gamma Rays; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D051379:Mice; D016688:Mice, Inbred NOD; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011836:Radiation Tolerance; D017382:Reactive Oxygen Species / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; D023181:Antimicrobial Cationic Peptides; C547500:RGLCYCRGRFCVCVG-NH(2); D017382:Reactive Oxygen Species; D003561:Cytarabine; D014212:Tretinoin