IL-1β inhibits self-renewal capacity of dormant CD34⁺/CD38⁻ acute myelogenous leukemia cells in vitro and in vivo.

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 p21 ^waf1, 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. [ABSTRACT FROM AUTHOR]

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