IL‐1β inhibits self‐renewal capacity of dormant CD34+/CD38− acute myelogenous leukemia cells in vitro and in vivo. Issue 8 (6th May 2013)

• Record Type: Journal Article
• Authors: Yang, Jing; Ikezoe, Takayuki; Nishioka, Chie; Nobumoto, Atsuya; Yokoyama, Akihito
• Is Part Of: International journal of cancer. Volume 133:Issue 8(2013:Oct. 15)
• Page Start: 1967
• Page End: 1981
• Publication Date: 2013-05-06
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28198
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>We previously showed that CD34<sup>+</sup>/CD38<sup>−</sup> 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<sup>+</sup>/CD38<sup>+</sup> counterparts. To identify candidate cytokines that are involved in the activation of JAK2/STAT5 in CD34<sup>+</sup>/CD38<sup>−</sup> AML cells, we compared the cytokine expression profiles of CD34<sup>+</sup>/CD38<sup>−</sup> AML cells and their CD34<sup>+</sup>/CD38<sup>+</sup> counterparts. Interestingly, freshly isolated CD34<sup>+</sup>/CD38<sup>−</sup> AML cells from patients (<italic>n</italic> = 17) expressed less interleukin‐1β (IL‐1β) than their CD34<sup>+</sup>/CD38<sup>+</sup> counterparts and CD34<sup>+</sup> normal hematopoietic stem/progenitor cells from healthy volunteers (<italic>n</italic> = 6), as measured by real‐time Reverse Transcription‐Polymerase Chain Reaction (RT‐PCR). Methylation‐specific PCR found that <italic>IL‐1B</italic> gene expression was silenced by methylation of the promoter region. Importantly, exposure of CD34<sup>+</sup>/CD38<sup>−</sup> 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 p21<italic><sup>waf1</sup></italic>, antiapoptotic proteins and p‐STAT5. Forced expression of IL‐1β in CD34<sup>+</sup>/CD38<sup>−</sup> AML cells by lentiviral transduction significantly impaired the self‐renewal capacity of the cells and induced apoptosis. Additionally, when these CD34<sup>+</sup>/CD38<sup>−</sup> 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.</p> </abstract>