Intracellular IL-23R is necessary for mitotic spindle formation and viability in AML

Interleukin-23 receptor (IL-23R) is a cell surface cytokine receptor classically expressed on T cells, where it regulates T cell activation. Here, we discovered a novel intracellular localization and function for IL-23R in Acute Myeloid Leukemia (AML). Compared to normal hematopoietic cells, IL-23R was increased in primary AML samples. IL-23R was predominantly localized intracellularly in AML cells. BioID mass spectrometry identified mitotic spindle proteins as top interactors with IL-23R. We confirmed interaction between endogenous IL-23R and the mitotic spindle in AML cells and primary AML samples, and this interaction was mediated by IL-23R’s (S/T)x(I/L)P motif. Genetic depletion of IL-23R disrupted mitotic spindle formation and reduced proliferation and stem cell/progenitor function of AML cell lines and primary AML samples. In contrast, depletion of IL-23R spared normal hematopoietic cells and progenitors. Thus, we discovered a novel intracellular function for IL-23R where this receptor regulates mitotic spindle formation and the growth of AML cells.