Autocrine interleukin-1 beta production in leukemia: Evidence for the involvement of mutated RAS

作者：Beaupre DM; Talpaz M; Marini FC; Cristiano RJ; Roth JA; Estrov Z; Albitar M; Freedman MH; Kurzrock R^*

来源：Cancer Research, 1999, 59(12): 2971-2980.

Interleukin (IL)-1 beta is constitutively expressed in many leukemias and operates as an autocrine growth factor. To study the cellular basis for this aberrant production, we analyzed two cell lines, B1 (acute lymphoblastic leukemia) and W1 (juvenile chronic myelogenous leukemia), which express high levels of IL-IP and have mutations in the K-RAS and N-RAS genes, respectively. Electromobility shift assays demonstrated transcription factor binding at multiple IL-1 beta promoter elements [nuclear factor (NF)-IL6/CREB, NFB1, NF kappa B, and NF-IL6], consistent with the activation of an upstream signaling pathway. To determine whether activated Ras was involved, two structurally distinct classes of farnesyltransferase (FTase) inhibitors (the monoterpenes and a peptidomimetic) and an adenoviral vector expressing antisense targeted to K-RAS were used to specifically interfere with Ras function and/or expression. Treatment with the FTase inhibitors resulted in a concentration-dependent decrease in both NF-IL6/CREB binding to the IL-1 beta promoter and IL-1 beta protein levels, without a significant change in total cellular protein levels. Furthermore, exposure of the B1 cells to antisense against K-RAS resulted in an approximately 50% reduction in both p21(Ras) and IL-1 beta protein levels. Growth suppression was observed after FTase inhibitor or antisense exposure, an effect that was partially reversible by the addition of recombinant IL-1 beta to the cultures, Our observations suggest that mutated RAS genes may mediate autocrine IL-1 beta production in some leukemias by stimulating signal transduction pathways that activate the IL-1 beta promoter.

• 出版日期1999-6-15