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

作者：Bonnet Melanie; Loosveld Marie; Montpellier Bertrand; Navarro Jean Marc; Quilichini Benoit; Picard Christophe; Di Cristofaro Julie; Bagnis Claude; Fossat Chantal; Hernandez Lucie; Mamessier Emilie; Roulland Sandrine; Morgado Ester; Formisano Treziny Christine; Dik Willem A; Langerak Anton W; Prebet Thomas; Vey Norbert; Michel Gerard; Gabert Jean; Soulier Jean; Macintyre Elizabeth A; Asnafi Vahid; Payet Bornet Dominique; Nadel Bertrand^*

来源：Blood, 2011, 117(24): 6650-6659.

DOI：10.1182/blood-2011-02-336842

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)

• 出版日期2011-6-16