1. Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis
- Author
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Sorcha Forde, Brian J. P. Huntly, Joanna Alicja Krupka, Shamith A. Samarajiwa, G. A. Amos Burke, Sharon Barrans, Francesco Cucco, Ming-Qing Du, Martin R Turner, Eve Roman, Wei Meng, Reuben Tooze, Philip A. Beer, Jie Gao, Susanne Bornelöv, Nurmahirah Binte Mohammed Zaini, Daniel Painter, Peter J. Campbell, Alex E. Blain, Thomas Oellerich, George Giotopoulos, Chun Gong, Björn Häupl, P Zhou, Siu Kwan Sze, Jernej Ule, Daniel J. Hodson, Igor Ruiz de los Mozos, Nicholas Francis Grigoropoulos, Zelvera Usheva, Michael Screen, Ryan Asby, Suzanne D. Turner, Jamie D. Matthews, Vikki Rand, Cathy Burton, Michelle G.K. Tan, Krupka, Joanna [0000-0003-0369-0329], Giotopoulos, George [0000-0003-1390-6592], Borneloev, Susanne [0000-0001-9276-9981], Turner, Suzanne [0000-0002-8439-4507], Huntly, Brian [0000-0003-0312-161X], Samarajiwa, Shamith [0000-0003-1046-0601], Hodson, Daniel [0000-0001-6225-2033], and Apollo - University of Cambridge Repository
- Subjects
Male ,Proteome ,translation ,Gene Expression ,MYC ,DEAD-box RNA Helicases ,proteotoxic stress ,0302 clinical medicine ,Ecology,Evolution & Ethology ,Loss of Function Mutation ,Protein biosynthesis ,Child ,Aged, 80 and over ,B-Lymphocytes ,0303 health sciences ,Stem Cells ,Burkitt lymphoma ,Translation (biology) ,Middle Aged ,Endoplasmic Reticulum Stress ,RNA Helicase A ,Neoplasm Proteins ,Cell biology ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Child, Preschool ,030220 oncology & carcinogenesis ,DDX3X ,Female ,Genetics & Genomics ,Adult ,RNA helicase ,Lymphoma, B-Cell ,Adolescent ,Mice, Transgenic ,Biology ,Biochemistry & Proteomics ,Gene Expression Regulation, Enzymologic ,Minor Histocompatibility Antigens ,Proto-Oncogene Proteins c-myc ,Young Adult ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Biology ,B cell ,Aged ,Computational & Systems Biology ,030304 developmental biology ,Messenger RNA ,FOS: Clinical medicine ,Neurosciences ,Germinal center ,RNA ,Cell Biology ,medicine.disease ,germinal center ,Protein Biosynthesis ,Proteostasis ,Diffuse large B-cell lymphoma - Abstract
Summary DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.
- Published
- 2021