IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs

Area of Science:

• Cellular Stress Response
• Hematopoiesis
• Oncology

Background:

• Hematopoietic stem cells (HSPCs) face lifelong stress, requiring robust mechanisms to maintain blood cell production.
• Dysregulation of stress response pathways can contribute to the development of myeloid leukemias.
• The unfolded protein response (UPR) is a critical cellular stress management system.

Purpose of the Study:

• To investigate the role of the UPR sensor inositol-requiring enzyme-1α (IRE1α) in protecting hematopoietic stem and progenitor cells (HSPCs) against myeloid leukemogenesis.
• To elucidate the downstream mechanisms by which IRE1α signaling prevents leukemia.
• To identify potential therapeutic targets for acute myeloid leukemia (AML).

Main Methods:

• Utilized transcriptome analysis and genome-wide mapping of X-box binding protein-1 (XBP1) targets in HSPCs.
• Employed mouse models with IRE1α deficiency and myeloproliferative oncogenes to study AML development.
• Assessed the impact of XBP1 induction on leukemia stem cell programs and patient-derived AML cells.

Main Results:

• Identified IRE1α signaling, activated by NADPH oxidase-2, as a key regulator in HSPCs.
• Demonstrated that IRE1α-induced XBP1 represses pro-leukemogenic programs, including the Wnt-β-catenin pathway.
• Discovered an '18-gene signature' of XBP1-repressed β-catenin targets associated with poor prognosis in AML.
• Showed that IRE1α deficiency accelerates AML development in mice, while XBP1 induction suppresses leukemia stem cell activity.

Conclusions:

• IRE1α-XBP1 signaling acts as a critical safeguard in HSPCs, preventing myeloid leukemogenesis.
• This pathway restricts pro-leukemogenic programs, offering a novel therapeutic avenue for AML.
• Targeting the IRE1α-XBP1 axis may hold promise for treating acute myeloid leukemia.