Abstract 5248: Targeted suppression of interleukin-1 signaling inhibits growth of primary human acute myeloid leukemia cells

Abstract

Background: Acute myeloid leukemia (AML) represents the most common type of leukemia in adults and is associated with high morbidity and mortality. Targeted therapy represents a promising approach in AML with the potential for increased efficacy and reduced toxicity. Because recent studies have demonstrated that certain inflammatory cytokines known to suppress normal hematopoiesis have the opposite effect (ie. enhancing proliferation) on cell growth of AML cells, we systematically assessed the functional relevance of 90 cytokines and their receptors in primary human AML cells. Here we present a novel role of Interleukin-1 (IL-1) signaling in aberrant regulation of AML cell growth. Methods and Results: To identify functionally important cytokine signaling pathways in leukemia pathogenesis we took a two pronged approach. First, we quantified the growth of 45 primary AML patient samples against graded concentrations of 90 cytokines. Second, we employed a functional siRNA screen targeting 188 cytokine receptors that were found highly expressed in 140 primary leukemia samples by gene expression analysis. Using this approach we identified that IL-1 signaling had the most dramatic effect. Forty percent of AML samples exhibited a 5-25 fold increase in growth in the presence of IL-1α/β. Paradoxically, IL-1 suppressed growth of normal CD34+ cells. Silencing the IL-1 receptor, IL1R1, reduced the viability of these AML primary samples by 60%. Most IL-1 sensitive AML samples exhibit monocytic and myelomonocytic features; however, no correlation with specific somatic mutations has thus far been observed. IL-1 responsive samples are from patients with abnormally increased serum IL-1β levels (5 fold). Consistent with this, conditioned media from the mononuclear cells of these samples promote the growth of AML CD34+ cells. Deep sequencing of primary AML samples indicated that genes encoding signaling molecules of IL-1 pathway (IL1R1, IL1RAP, MYD88, TRAF6, IRAK, IKK, cJUN, NFκB and p38) are normal. We confirmed the importance of IL1R1 using a genetic model. We found that the absence of IL1R1 in murine bone marrow leads to significant ablation of clonogenic potential (80% reduction) of oncogene-induced leukemic cells (AML1-ETO9a, NRASG12D and MLL-ENL) when compared to oncogene-induced leukemic cells from wild type mice. However, no effect on colony growth was observed with empty vector controls. These results suggest that multiple genetic drivers of leukemia share a dysfunctional IL-1 pathway. Mechanistically, IL-1 promotes CD34+ AML cell survival by increasing p38 phosphorylation that is significantly inhibited with IL1R1 knockdown or p38 kinase inhibitors such as Doramapimod. No toxic effect of Doramapimod was observed on normal cell growth. Conclusion: These results demonstrate a novel role for IL-1 signaling in promoting oncogenesis in AML and provide evidence that targeting this pathway might be beneficial to AML patients. Citation Format: Anupriya Agarwal, Alyssa Carey, Elie Traer, Jeffrey Tyner, Grover C. Bagby, Brian J. Druker. Targeted suppression of interleukin-1 signaling inhibits growth of primary human acute myeloid leukemia cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5248. doi:10.1158/1538-7445.AM2014-5248

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

“…In agreement with previous reports using anti-IL-1 antibodies or the IL-1 receptor antagonist IL1RA (15,(17)(18)(19)(20)22), blocking IL-1 signaling with the IL1RAP-targeting antibody mAb3F8 significantly suppressed the proliferation of primary AML cells responsive to IL-1. The importance of IL-1 signaling in AML cells has recently obtained further support by a study that used a combined cytokine and siRNA screen against cell-surface receptors and identified IL-1 signaling inhibition as having the most dramatic effect on regulating growth of AML cells (38). Hence, based on available data, we propose that IL-1 signaling inhibition as a second mode of action in an antibody-based immunotherapy against IL1RAP should be important in the future treatment of AML.…”