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Acute myeloid leukaemia (AML) is an aggressive blood cancer characterised by uncontrolled growth of immature blood cells, with a 5-year survival rate of 23%, largely due to the persistence of leukemic stem cells (LSCs) that resist conventional treatments.

While stress responses in cancer are known to contribute to cell survival, the specific mechanisms in leukaemic stem cells (LSCs) remained poorly understood. Tajik et al. aimed to investigate the role of stress granules (SGs) – cellular condensates that form during cellular stress – in AML, particularly within the disease-initiating LSC population.

Their experimental approach combined multiple proteomic techniques, including BioID mass spectrometry, eCLIP sequencing, and RNA sequencing across multiple AML cell lines and patient samples. After loading samples in a Vanquish Neo, the mass spectrometry analysis was performed using a Bruker timsTOF SCP, with peptide separation on home-packed silica column or an IonOpticks Aurora Ultimate CSI 25×75 C18 UHPLC column. The researchers used both DDA-PASEF and DIA-PASEF methods, identifying over 800 potential AML-specific stress granule proteins.

The researchers discovered that stress granules are not just survival mechanisms but are fundamental to LSC integrity, governing cell fate through selective RNA regulation and protein interactions. This quantitative study also revealed that stress granules in AML, particularly in LSCs, play a critical role in suppressing pro-apoptotic and inflammatory transcripts through a novel mechanism involving G3BP1 and UPF1 proteins. By targeting highly structured RNA transcripts, these stress granules help AML cells survive chronic intrinsic stress.

This research opens new therapeutic avenues by demonstrating that targeting stress granules could provide an effective strategy against AML, potentially applicable to other stress-prone cancer types.

Publication
bioRxiv

Authors

Amanda Tajik, Emily Tsao, Soheil Jahangiri, Brendon Seale, Brian A. Yee, Jack T. Naritomi, Zaldy Balde, Severine Cathelin, Ava Keyvani Chahi, Lance Li, He Tian Chen, Nicholas Wong, Lina Liu, Pratik Joshi, Steven Moreira, Curtis W. McCloskey, Shahbaz Khan, Katherine L. Rothamel, Helena Boutzen, Suraj Bansal, Andy G.X. Zeng, Stefan Aigner, Yu Lu, John E. Dick, Thomas Kislinger, Rama Khokha, Mark D. Minden, Anne-Claude Gingras, Gene W. Yeo, & Kristin J. Hope

Title

Stress Granules Underlie Acute Myeloid Leukemia Stem Cell Survival and Stress Adaptation