Super-enhancer landscape reveals leukemia stem cell reliance on X-box binding protein 1 as a therapeutic vulnerability

Relapse of patients with chronic myelogenous leukemia (CML) may occur at least partially because of leukemia stem cells (LSCs) lack of sensitivity to tyrosine kinase inhibitors (TKIs) such as imatinib. The precise regulation of LSC stemness is incompletely understood. Given that traits of LSCs are subject to epigenetic regulation, we hypothesized that LSCs might be dependent on continuous active transcription of genes associated with super enhancers (SEs), which might in turn suggest an opportunity for intervention. In this study, we tested this hypothesis and delineated the SE landscape in LSCs using patient derived CML LSCs in vitro and in mouse models. Disruption of the SE associated transcriptional addiction by THZ1, a covalent cyclin dependent kinase 7 (CDK7) inhibitor, efficiently eradicated LSCs in CML bearing mice while sparing normal hematopoietic stem cells. Furthermore, we found that X box binding protein 1 (XBP1), a substrate of mRNA splicing endonuclease IRE1 in the unfolded protein response pathway, was a SE associated oncogene in LSCs. Either knockdown of XBP1 or hematopoietic cell specific Ire1 conditional knockout in mice impaired maintenance of CML LSCs. Overall, we identified an epigenetic transcriptional program in LSCs, adding to evidence for the theory of oncogene addiction and suggesting a potential targeting strategy for CML.