Abstract
Genetic or pharmacologic inhibition of the IRE1–XBP1 pathway delays CLL progression in mice.
Major finding: Genetic or pharmacologic inhibition of the IRE1–XBP1 pathway delays CLL progression in mice.
Concept: IRE1–XBP1 pathway inhibition compromises BCR signaling and induces CLL apoptosis.
Impact: IRE1–XBP1 inhibition in combination with ibrutinib may be a potential treatment strategy for CLL.
Activation of the ER stress response is an adaptive mechanism that can promote cancer cell survival. Given that ER stress response activation has recently been implicated in survival of chronic lymphocytic leukemia (CLL) cells, Tang and colleagues directly examined the role of the most conserved ER stress response pathway, comprised of the transcription factor X-box binding protein 1 (XBP1) and its upstream activator inositol-requiring enzyme 1 (IRE1), in CLL progression in vivo using a B cell–specific Xbp1-deficient CLL mouse model. Interestingly, Xbp1−/− mice exhibited a significant delay in leukemic progression that was associated with reduced spleen enlargement and improved survival. Mechanistically, Xbp1-null cells showed attenuated activation of the B-cell antigen receptor (BCR), reduced secretion of IgM, and higher cell surface expression of sphingosine-1-phosphate receptor, suggesting that XBP1 deficiency might contribute to delayed leukemic progression by disrupting survival and homing signals and facilitating the exit of CLL cells from the spleen and lymph nodes. To pharmacologically target XBP1, the authors developed B-I09, a potent small-molecule IRE1 RNase inhibitor that blocks the mRNA splicing of XBP1 that is required for its activation, and found that it effectively suppressed primary mouse and human CLL growth in vitro without affecting the synthesis, assembly, or transport of critical B-cell integral membrane proteins. In the CLL mouse model, B-I09 treatment suppressed leukemic progression by inducing apoptosis of CLL cells, and like Xbp1 deficiency, compromised BCR signaling, as shown by reduced activation of Bruton tyrosine kinase (BTK). Notably, B-I09 synergized with ibrutinib, a BTK inhibitor that has shown promise in the treatment of B-cell malignancies, to suppress growth of human CLL, multiple myeloma, and mantle cell lymphoma cell lines. These findings implicate the IRE1–XBP1 pathway in CLL progression and provide a rationale for clinical evaluation of combined IRE1 and BTK inhibition in patients with CLL.
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