RNA sequestration in P-bodies sustains myeloid leukaemia
Por:
Kodali, S, Proietti, L, Valcarcel, G, López-Rubio, AV, Pessina, P, Eder, T, Shi, JC, Jen, AN, Lupión-Garcia, N, Starner, AC, Bartels, MD, Cui, YZ, Sands, CM, Planas-Riverola, A, Martínez, A, Velasco-Hernandez, T, Tomás-Daza, L, Alber, B, Manhart, G, Mayer, IM, Kollmann, K, Fatica, A, Menendez, P, Shishkova, E, Rau, RE, Javierre, BM, Coon, J, Chen, Q, Van Nostrand, EL, Sardina, JL, Grebien, F and Di Stefano, B
Publicada:
1 oct 2024
Ahead of Print:
1 ago 2024
Resumen:
Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and future therapeutic interventions.
Filiaciones:
Kodali, S:
Baylor Coll Med, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA
Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
Baylor Coll Med, Dan Duncan Comprehens Canc Ctr, Houston, TX 77030 USA
Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA
Proietti, L:
Univ Vet Med Vienna, Inst Med Biochem, Vienna, Austria
Valcarcel, G:
Josep Carreras Leukaemia Res Inst, Badalona, Spain
López-Rubio, AV:
Josep Carreras Leukaemia Res Inst, Badalona, Spain
Pessina, P:
Baylor Coll Med, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA
Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
Baylor Coll Med, Dan Duncan Comprehens Canc Ctr, Houston, TX 77030 USA
Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA
Eder, T:
Univ Vet Med Vienna, Inst Med Biochem, Vienna, Austria
Shi, JC:
Univ Calif Riverside, Sch Med, Div Biomed Sci, Riverside, CA USA
Jen, AN:
Univ Wisconsin, Dept Biomol Chem, Madison, WI USA
Lupión-Garcia, N:
Baylor Coll Med, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA
Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
Baylor Coll Med, Dan Duncan Comprehens Canc Ctr, Houston, TX 77030 USA
Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA
Starner, AC:
Baylor Coll Med, Verna & Marrs McLean Dept Biochem, Houston, TX USA
Bartels, MD:
Baylor Coll Med, Verna & Marrs McLean Dept Biochem, Houston, TX USA
Cui, YZ:
Baylor Coll Med, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA
Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
Baylor Coll Med, Dan Duncan Comprehens Canc Ctr, Houston, TX 77030 USA
Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA
Sands, CM:
Baylor Coll Med, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA
Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
Baylor Coll Med, Dan Duncan Comprehens Canc Ctr, Houston, TX 77030 USA
Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA
Planas-Riverola, A:
Josep Carreras Leukaemia Res Inst, Badalona, Spain
Martínez, A:
Josep Carreras Leukaemia Res Inst, Badalona, Spain
:
Josep Carreras Leukaemia Res Inst, Badalona, Spain
Tomás-Daza, L:
Josep Carreras Leukaemia Res Inst, Badalona, Spain
Alber, B:
Univ Vet Med Vienna, Inst Med Biochem, Vienna, Austria
Manhart, G:
Univ Vet Med Vienna, Inst Med Biochem, Vienna, Austria
Mayer, IM:
Univ Vet Med Vienna, Inst Pharmacol & Toxicol, Vienna, Austria
Kollmann, K:
Univ Vet Med Vienna, Inst Pharmacol & Toxicol, Vienna, Austria
Fatica, A:
Sapienza Univ Rome, Dept Biol & Biotechnol Charles Darwin, Rome, Italy
:
Josep Carreras Leukaemia Res Inst, Badalona, Spain
Shishkova, E:
Univ Wisconsin, Dept Biomol Chem, Madison, WI USA
Natl Ctr Quantitat Biol Complex Syst, Madison, WI USA
Rau, RE:
Baylor Coll Med, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA
Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
Baylor Coll Med, Texas Childrens Hosp, Dept Pediat, Houston, TX USA
:
Josep Carreras Leukaemia Res Inst, Badalona, Spain
Coon, J:
Univ Wisconsin, Dept Biomol Chem, Madison, WI USA
Natl Ctr Quantitat Biol Complex Syst, Madison, WI USA
Univ Wisconsin, Dept Chem, Madison, WI USA
Mor, Madison, WI USA
Chen, Q:
Univ Utah, Dept Surg, Mol Med Program, Div Urol,Sch Med, Salt Lake City, UT USA
Van Nostrand, EL:
Baylor Coll Med, Verna & Marrs McLean Dept Biochem, Houston, TX USA
:
Josep Carreras Leukaemia Res Inst, Badalona, Spain
Grebien, F:
Univ Vet Med Vienna, Inst Med Biochem, Vienna, Austria
St Anna Childrens Canc Res Inst CCRI, Vienna, Austria
Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria
Di Stefano, B:
Baylor Coll Med, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA
Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
Baylor Coll Med, Dan Duncan Comprehens Canc Ctr, Houston, TX 77030 USA
Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA
Baylor Coll Med, Mol Biol & Therapeut Innovat Ctr, Houston, TX USA
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