XBP1 promotes NRAS(G12D) pre‐B acute lymphoblastic leukaemia through IL‐7 receptor signalling and provides a therapeutic vulnerability for oncogenic RAS

Activating point mutations of the RAS gene act as driver mutations for a subset of precursor‐B cell acute lymphoblastic leukaemias (pre‐B ALL) and represent an ambitious target for therapeutic approaches. The X box‐binding protein 1 (XBP1), a key regulator of the unfolded protein response (UPR), is critical for pre‐B ALL cell survival, and high expression of XBP1 confers poor prognosis in ALL patients. However, the mechanism of XBP1 activation has not yet been elucidated in RAS mutated pre‐B ALL. Here, we demonstrate that XBP1 acts as a downstream linchpin of the IL‐7 receptor signalling pathway and that pharmacological inhibition or genetic ablation of XBP1 selectively abrogates IL‐7 receptor signalling via inhibition of its downstream effectors, JAK1 and STAT5. We show that XBP1 supports malignant cell growth of pre‐B NRAS(G12D) ALL cells and that genetic loss of XBP1 consequently leads to cell cycle arrest and apoptosis. Our findings reveal that active XBP1 prevents the cytotoxic effects of a dual PI3K/mTOR pathway inhibitor (BEZ235) in pre‐B NRAS(G12D) ALL cells. This implies targeting XBP1 in combination with BEZ235 as a promising new targeted strategy against the oncogenic RAS in NRAS(G12D)‐mutated pre‐B ALL.