IFITM3 Enhances PI3K Pathway Signaling to Promote B-cell Malignancies

Although IFITM3 is primarily known for its role in preventing viral infection, there is now evidence that IFITM3 is overexpressed in a variety of cancers, with greater expression levels being associated with higher histopathologic grade and stage. Lee and colleagues found that Ifitm3^−/− mice had much lower surface expression of the B-cell receptor CD19 on their pre-B cells than wild-type (WT) mice. This low level of CD19 was accompanied by increased apoptosis, decreased proliferation, and reduced PI3K signaling, consistent with CD19′s role in promoting PI3K signaling. When oncogenically transformed via BCR–ABL1 fusion and NRAS^G12D mutation, pre-B cells from Ifitm3^−/− mice exhibited reduced survival and proliferation compared with WT transformed pre-B cells, and Ifitm3^−/− B-cell acute lymphoblastic leukemia cells were incapable of inducing overt leukemia when transplanted into immunodeficient recipient mice. However, expression of the phosphomimetic mutant IFITM3^Y20E, a variant that has previously been shown to prevent endocytosis, restored the ability of pre-B cells to initiate leukemia in mice. Mechanistically, IFITM3^Y20E caused oncogenic PI3K pathway signaling by acting as a scaffold to facilitate accumulation of the PI3K product PIP₃ via interactions between PIP₃ and two IFITM3 lysine residues (K83 and K104), which reside in IFITM3′s evolutionarily conserved intracellular loop. Notably, lipid rafts in Ifitm3^−/− B cells had substantially reduced levels of PIP₃, leading to decreases in more than 60 lipid raft–associated cell-surface receptors and defects in B-cell receptor signaling and cell adhesion. Collectively, these findings characterize a cancer-related function for IFITM3 that is independent of its established effects on cholesterol and suggest that IFITM3 may be a target of interest in B-cell malignancies.

Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, et al. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature 2020;588:491–7.

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