美国国立卫生研究院Stanley Adoro研究组发现，IRE1α–XBP1通过限制促白血病基因程序来保护造血干细胞和祖细胞。相关论文于2025年1月9日在线发表在《自然—免疫学》杂志上。

研究人员揭示了未折叠蛋白反应应激传感器肌醇需求酶-1α（IRE1α）在造血干细胞和祖细胞（HSPC）中的信号作用，其可作为防御髓系白血病发生的保护机制。IRE1α部分通过NADPH氧化酶-2机制激活，诱导X-box结合蛋白-1（XBP1）介导的抑制作用，并抑制了以Wnt-β-连环蛋白通路为代表的促白血病基因程序。转录组分析和XBP1靶标在HSPC中的全基因组定位揭示了XBP1抑制的β-连环蛋白靶标的“18基因特征”，这些基因在预后较差的急性髓系白血病（AML）病例中高表达。

因此，IRE1α缺乏与造血增生性致癌基因在HSPC中的合作导致小鼠致命性AML，而XBP1的遗传诱导则抑制了白血病干细胞程序和患者来源的AML细胞的活性。因此，IRE1α–XBP1信号通过限制HSPC中的促白血病基因程序，保护了血液系统的完整性。

研究人员表示，造血干细胞必须应对各种压力源，以确保正常的血细胞生成。

附：英文原文

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

Author: Barton, Brendan M., Son, Francheska, Verma, Akanksha, Bal, Saswat Kumar, Tang, Qianzi, Wang, Rui, Umphred-Wilson, Katharine, Khan, Rehan, Trichka, Josephine, Dong, Han, Lentucci, Claudia, Chen, Xi, Chen, Yinghua, Hong, Yuning, Duy, Cihangir, Elemento, Olivier, Melnick, Ari M., Cao, Jin, Chen, Xi, Glimcher, Laurie H., Adoro, Stanley

Issue&Volume: 2025-01-09

Abstract: Hematopoietic stem cells must mitigate myriad stressors throughout their lifetime to ensure normal blood cell generation. Here, we uncover unfolded protein response stress sensor inositol-requiring enzyme-1α (IRE1α) signaling in hematopoietic stem and progenitor cells (HSPCs) as a safeguard against myeloid leukemogenesis. Activated in part by an NADPH oxidase-2 mechanism, IRE1α-induced X-box binding protein-1 (XBP1) mediated repression of pro-leukemogenic programs exemplified by the Wnt–β-catenin pathway. Transcriptome analysis and genome-wide mapping of XBP1 targets in HSPCs identified an ‘18-gene signature’ of XBP1-repressed β-catenin targets that were highly expressed in acute myeloid leukemia (AML) cases with worse prognosis. Accordingly, IRE1α deficiency cooperated with a myeloproliferative oncogene in HSPCs to cause a lethal AML in mice, while genetic induction of XBP1 suppressed the leukemia stem cell program and activity of patient-derived AML cells. Thus, IRE1α–XBP1 signaling safeguards the integrity of the blood system by restricting pro-leukemogenic programs in HSPCs.

DOI: 10.1038/s41590-024-02063-w

Source: https://www.nature.com/articles/s41590-024-02063-w