Deletion 6q drives T-cell leukemia progression by ribosome modulation [Research Articles]

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 a Tal1/Lmo1/Notch1-driven mouse model of leukemogenesis, demonstrating the tumor suppressor nature of the two-gene region. Proteomic and translation 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 co-extinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosome and mitochondria in T-ALL tumor progression.

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