posted on 2023-04-03, 22:00authored byStéphanie Gachet, Tiama El-Chaar, David Avran, Eulalia Genesca, Frédéric Catez, Samuel Quentin, Marc Delord, Gabriel Thérizols, Delphine Briot, Godelieve Meunier, Lucie Hernandez, Marika Pla, Willem K. Smits, Jessica G. Buijs-Gladdines, Wouter Van Loocke, Gerben Menschaert, Isabelle André-Schmutz, Tom Taghon, Pieter Van Vlierberghe, Jules P. Meijerink, André Baruchel, Hervé Dombret, Emmanuelle Clappier, Jean-Jacques Diaz, Claude Gazin, Hugues de Thé, François Sigaux, Jean Soulier
Differentially Expressed Proteins Deleted versus non-deleted clones
Funding
ERC
Ligue Contre le Cancer
Saint-Louis Institute
ANR
History
ARTICLE ABSTRACT
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression.
The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome–mitochondria axis, suggesting the potential for therapeutic intervention.This article is highlighted in the In This Issue feature, p. 1494