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Cancer Discov. 2018 Dec;8(12):1614-1631. doi: 10.1158/2159-8290.CD-17-0831. Epub 2018 Sep 28.

Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation.

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INSERM UMR944 and CNRS UMR7212, Hôpital Saint-Louis, Paris, France.
Institute of Hematology (IUH), Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Hematology Laboratory APHP, Hôpital Saint-Louis, Paris, France.
Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS 5286, Centre Léon Bérard; Université Lyon 1, Lyon, France.
INSERM UMRS 940, Hôpital Saint-Louis, Paris, France.
Department of Pediatric Oncology/Hematology, Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Cancer Research Institute, Ghent University, Ghent, Belgium.
U1163 INSERM, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
Hematology Pediatry Department, Robert Debré Hospital, Paris, France.
Hematology Department, Hôpital Saint-Louis, Paris, France.
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, Direction de La Recherche Fondamentale, CEA, Evry, France.
INSERM UMR944 and CNRS UMR7212, Hôpital Saint-Louis, Paris, France.
Contributed equally


: 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. SIGNIFICANCE: 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.

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