title: IL-1β inhibits self-renewal capacity of dormant CD34⁺/CD38⁻ acute myelogenous leukemia cells in vitro and in vivo.
abstract: We previously showed that CD34⁺/CD38⁻ acute myelogenous leukemia (AML) cells, which contain leukemia stem cells, expressed a greater amount of the phosphorylated forms of JAK2 and STAT5 (p-JAK2 and p-STAT5) than their CD34⁺/CD38⁺ counterparts. To identify candidate cytokines that are involved in the activation of JAK2/STAT5 in CD34⁺/CD38⁻ AML cells, we compared the cytokine expression profiles of CD34⁺/CD38⁻ AML cells and their CD34⁺/CD38⁺ counterparts. Interestingly, freshly isolated CD34⁺/CD38⁻ AML cells from patients (n = 17) expressed less interleukin-1β (IL-1β) than their CD34⁺/CD38⁺ counterparts and CD34⁺ normal hematopoietic stem/progenitor cells from healthy volunteers (n = 6), as measured by real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Methylation-specific PCR found that IL-1B gene expression was silenced by methylation of the promoter region. Importantly, exposure of CD34⁺/CD38⁻ AML cells to IL-1β (100 ng/ml) stimulated cell-cycle progression, induced apoptosis and sensitized these cells to growth inhibition by antileukemia agents. These changes occurred in conjunction with the downregulation of cyclin-dependent kinase inhibitor p21waf1, antiapoptotic proteins and p-STAT5. Forced expression of IL-1β in CD34⁺/CD38⁻ AML cells by lentiviral transduction significantly impaired the self-renewal capacity of the cells and induced apoptosis. Additionally, when these CD34⁺/CD38⁻ AML cells with forced expression of IL-1β were transplanted into severely immunocompromised mice, the engraftment of the cells and reconstitution of AML were significantly impaired. Taken together, our results indicate that the inhibition of STAT5 by IL-1β may be a promising treatment strategy to eradicate leukemia stem cells in AML.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Atsuya
authors.initials: A
authors.lastname: Nobumoto
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D019175:DNA Methylation; D015536:Down-Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D018952:Antigens, CD34; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053583:Interleukin-1beta; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051997:ADP-ribosyl Cyclase 1
keywords: IL-1β; STAT5; leukemia stem cells; quiescence