Posttranscriptional deregulation of MYC via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia

M Bonnet, M Loosveld, B Montpellier, JM Navarro, B Quilichini, C Picard, J Di Cristofaro, C Bagnis, C Fossat, L Hernandez, E Mamessier, S Roulland, E Morgado, C Formisano-Treziny, Wim Dik, Ton Langerak, T Prebet, N Vey, G Michel, J GabertJ Soulier, EA Macintyre, V Asnafi, D Payet-Bornet, B Nadel

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64 Citations (Scopus)

Abstract

Cumulative evidence indicates that MYC, one of the major downstream effectors of NOTCH1, is a critical component of T-cell acute lymphoblastic leukemia (T-ALL) oncogenesis and a potential candidate for targeted therapy. However, MYC is a complex oncogene, involving both fine protein dosage and cell-context dependency, and detailed understanding of MYC-mediated oncogenesis in T-ALL is still lacking. To better understand how MYC is interspersed in the complex T-ALL oncogenic networks, we performed a thorough molecular and biochemical analysis of MYC activation in a comprehensive collection of primary adult and pediatric patient samples. We find that MYC expression is highly variable, and that high MYC expression levels can be generated in a large number of cases in absence of NOTCH1/FBXW7 mutations, suggesting the occurrence of multiple activation pathways in addition to NOTCH1. Furthermore, we show that posttranscriptional deregulation of MYC constitutes a major alternative pathway of MYC activation in T-ALL, operating partly via the PI3K/AKT axis through down-regulation of PTEN, and that NOTCH1(m) might play a dual transcriptional and posttranscriptional role in this process. Altogether, our data lend further support to the significance of therapeutic targeting of MYC and/or the PTEN/AKT pathways, both in GSI-resistant and identified NOTCH1-independent/MYC-mediated T-ALL patients. (Blood. 2011;117(24):6650-6659)
Original languageUndefined/Unknown
Pages (from-to)6650-6659
Number of pages10
JournalBlood
Volume117
Issue number24
DOIs
Publication statusPublished - 2011

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