Tajik, Amanda, Tsao, Emily, Seale, Brendon, Jahangiri, Soheil, Abidin, Belma, Liu, Lina, Balde, Zaldy, Chen, He Tian (Tony), Wong, Nicholas, Keyvani Chahi, Ava, Joshi, Pratik, Moreira, Steven, McCloskey, Curtis W., Khan, Shahbaz, Boutzen, Helena, Wong, Cassandra, Bansal, Suraj, Zeng, Andy G.X., Aigner, Stefan, Lu, Yu, Dick, John E., Kislinger, Thomas, Khokha, Rama, Minden, Mark D., Yeo, Gene W., Gingras, Anne-Claude, and Hope, Kristin J.
The development of novel leukemic stem cell (LSC)-targeted therapeutics, which spare hematopoietic stem cells (HSC), is an urgent goal towards reducing the high, LSC-driven, relapse rates in acute myeloid leukemia (AML) patients. Towards elucidating key post-transcriptional networks underlying LSC maintenance we previously performed an in vivo pooled CRISPR dropout screen targeting 128 RNA binding proteins (RBPs) highly expressed in AML LSCs while having low expression in HSCs. This screen highlighted 12 RBPs crucial for murine AML LSC-mediated leukemic growth, of which there was a significant enrichment of stress granule (SG) RBPs. Further, gene set enrichment analysis shows the SG proteome is enriched in human AML LSCs vs non-LSCs while normal HSCs have reduced SG RBP expression relative to multipotent progenitor cells. SGs are dynamic biomolecular condensates, composed of ribonucleoprotein complexes, which may form as a protective mechanism against a variety of stress conditions. SGs are gaining increasing attention as contributors to cancer metastasis and chemoresistance, but their role in LSCs is virtually unexplored.