Panoply™ Human IL1R1 Knockdown Stable Cell Line

Secreted proteins within the bone marrow microenvironment play a key role in acute myeloid leukemia (AML). Ex vivo functional screening of 94 cytokines revealed that the proinflammatory cytokine interleukin-1 (IL-1) induces significant expansion of myeloid progenitor cells in approximately 67% of AML patients while suppressing the growth of normal progenitor cells. IL-1β and IL-1 receptor levels are elevated in AML patients, and silencing the IL-1 receptor significantly inhibits clonogenicity and disease progression in vivo. IL-1 promotes AML cell growth by enhancing p38 MAPK phosphorylation and promoting the secretion of multiple other growth factors and inflammatory cytokines. Treatment with a p38 MAPK inhibitor reverses these effects and allows normal CD34+ cells to recover from IL-1-mediated growth inhibition. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for the clinical development of therapeutics targeting the IL-1/IL1R1/p38MAPK pathway in AML.

To elucidate the specific role of IL-1 signaling in AML, researchers sought to determine the functional significance of IL1R1. Here, they found that cell growth was reduced approximately 2-fold and clonogenicity was reduced 3.5-fold in IL1R1 knockdown primary AML cells and cell lines(Figure 1A), but this effect was absent in IL-1-insensitive AML samples. The importance of IL1R1 in AML cell clonogenicity was further demonstrated using Il1R1-deficient and wild-type mouse bone marrow transduced with oncogenes implicated in AML pathogenesis (AML1-ETO9a coupled to NRASG12D or MLL-ENL). Compared with wild-type cells, myeloid clonogenicity was significantly reduced in cells transduced with the Il1R1-null oncogene, whether cultured in cytokine-supplemented medium with IL-1β (2.5-fold reduction) or IL-1β alone (4-fold reduction) (Figure 1B). In contrast, no significant effect on clonogenic growth was observed in empty vector controls (Figure 1B). Furthermore, immunophenotyping of the bone marrow of wild-type and Il1r1 null mice revealed no significant differences in stem and progenitor cell populations. Altogether, these results suggest that IL1R1 is not essential for normal hematopoiesis but can regulate the growth of AML cells.

Figure 1. Absence of IL1R1 Attenuates the Growth of Primary AML Cells, as well as Colony-Forming Ability and Disease Progression, in a Murine AML Bone Marrow Transduction or Transplantation Model. (Carey A, et al., 2017)