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

Published in: Blood, 2011, 117 (24), pp.6650-6659. ⟨10.1182/blood-2011-02-336842⟩

Authors: Mélanie Bonnet, Marie Loosveld, Bertrand Montpellier, Jean-Marc Navarro, Benoit Quilichini, Christophe Picard, Julie Di Cristofaro, Claude Bagnis, Chantal Fossat, Lucie Hernandez, Emilie Mamessier, Sandrine Roulland, Ester Morgado, Christine Formisano-Tréziny, Willem Dik, Anton Langerak, Thomas Prebet, Norbert Vey, Gérard Michel, Jean Gabert, Jean Soulier, Elizabeth Macintyre, Vahid Asnafi, Dominique Payet-Bornet, Bertrand Nadel

Summary

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 NOTCH1m 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.

Link to Pubmed [PMID] – 21527520

Link to HAL – amu-03606489

Link to DOI – 10.1182/blood-2011-02-336842