3044 – SUPPRESSION OF ACUTE MYELOID LEUKEMOGENESIS BY A NONCANONICAL IRE1Α-XBP1 SIGNALING MECHANISM

• Published in: Experimental hematology 2021-08, Vol.100, p.S63-S63
• Main Authors: Adoro, Stanley, Barton, Brendan, Bal, Saswat Kumar, Son, Francheska
• Format: Article
• Language: English
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2021.12.263

Most patients with AML achieve clinical remission after chemotherapy but eventually die from disease relapse as they, in part, succumb to chemotherapy-resistant leukemia stem cells (LSC) which persist and often reinitiate a more lethal AML, sometimes years after remission. While eliminating LSCs has become a desirable strategy to achieve durable AML remission, much remains unknown about LSC-specific programs and their vulnerabilities. Increasing evidence show that disruptions in proteome homeostasis or “proteostasis” can determine HSC integrity and the emergence of malignancy. Thus, we interrogated AML cell fractions (blasts and LSCs) for expression and activity of the highly conserved endoplasmic reticulum enzyme IRE1α, a key mediator of the unfolded protein response that promotes proteostasis in eukaryotic cells. Activated IRE1α catalyzes a non-conventional splicing of the XBP1 mRNA to generate a transcript that encodes the transcription factor XBP1, the main effector of IRE1α-transduced signals. We found that contrary to blast cells, purified primary human LSCs from multiple AML patient cohorts expressed strikingly diminished levels of IRE1α-XBP1, prompting us to test in patient-derived (PDX) human AML and genetic mouse models that downregulated expression of this pathway might facilitate acute myeloid leukemogenesis. Indeed, genetic induction of XBP1 in patient-derived AML cells suppressed their LSC transcriptional signature, impaired their clonogenic capacity, and limited AML disease in immunodeficient animals. By contrast, genetically engineered IRE1α or XBP1 insufficiency in HSC progenitors cooperated with the myeloproliferative oncogene FLT3-ITD to cause a lethal AML disease in mice. Mechanistically, we discovered a noncanonical activity of IRE1α-induced XBP1 as a potent transcriptional repressor of signature LSC programs, exemplified by the β-catenin/TCF pathway that promotes cancer stem cell homeostasis. Collectively, our study reveals a leukemia suppression function for IRE1α-XBP1 in HSC progenitors that restrains acute myeloid leukemogenesis.