PRMT1-Mediated Metabolic Reprogramming Promotes Leukemogenesis

Su, H.; Sun, Y.; Guo, H.; Sun, C.-w.; Chen, Q.; Liu, S.; Li, A.; Gao, M.; Zhao, R.; Raffel, G.; Jin, J.; Qu, C.-K.; Yu, M.; Klug, C. A.; Zheng, Y. G.; Ballinger, S.; Kutny, M.; Long Zheng, X.; Chong, Z.; Senevirathne, C.; Gross, S.; Chen, Y.; Luo, M.; Zhao, X.

doi:10.1101/2024.12.12.628174

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bioRxiv · 10.1101/2024.12.12.628174

PRMT1-Mediated Metabolic Reprogramming Promotes Leukemogenesis

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Abstract

Copious expression of protein arginine methyltransferase 1 (PRMT1) is associated with poor survival in many types of cancers, including acute myeloid leukemia. We observed that a specific acute megakaryocytic leukemia (AMKL) cell line (6133) derived from RBM15-MKL1 knock-in mice exhibited heterogeneity in Prmt1 expression levels. Interestingly, only a subpopulation of 6133 cells expressing high levels of Prmt1 caused leukemia when transplanted into congenic mice. The PRMT1 inhibitor, MS023, effectively cured this PRMT1-driven leukemia. Seahorse analysis revealed that PRMT1 increased the extracellular acidification rate (ECAR) and decreased the oxygen consumption rate (OCR). Consistently, PRMT1 accelerated glucose consumption and led to the accumulation of lactic acid in the leukemia cells. The metabolomic analysis supported that PRMT1 stimulated the intracellular accumulation of lipids, which was further validated by FACS analysis with BODIPY 493/503. In line with fatty acid accumulation, PRMT1 downregulated the protein level of CPT1A, which is involved in the rate-limiting step of fatty acid oxidation. Furthermore, administering the glucose analogue 2-deoxy-glucose (2-DG) delayed AMKL progression and promoted cell differentiation. Ectopic expression of Cpt1a rescued the proliferation of 6133 cells ectopically expressing PRMT1 in the glucose-minus medium. In conclusion, PRMT1 upregulates glycolysis and downregulates fatty acid oxidation to enhance the proliferation capability of AMKL cells. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/628174v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1ae96borg.highwire.dtl.DTLVardef@d27916org.highwire.dtl.DTLVardef@ba63corg.highwire.dtl.DTLVardef@cee9af_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Su, H., Sun, Y., Guo, H., Sun, C.-w., Chen, Q., Liu, S., Li, A., Gao, M., Zhao, R., Raffel, G., Jin, J., Qu, C.-K., Yu, M., Klug, C. A., Zheng, Y. G., Ballinger, S., Kutny, M., Long Zheng, X., Chong, Z., Senevirathne, C., Gross, S., Chen, Y., Luo, M., Zhao, X.. 2024-12-17. PRMT1-Mediated Metabolic Reprogramming Promotes Leukemogenesis. https://doi.org/10.1101/2024.12.12.628174

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