Post transcriptional deregulation of MYC Via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia
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2010
- handle: 10670/1.u5ar6d
- halshs: halshs-00739620
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hematologySujets proches
Deregulation--Law and legislation Regulatory reform Industries--Deregulation Leukemia, Lymphoblastic Acute lymphocytic leukemia Expressive behavior Tumorigenesis Pathogenesis of cancer Cancer--Pathogenesis OncogenesisCiter ce document
Mélanie Bonnet et al., « Post transcriptional deregulation of MYC Via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia », HALSHS : archive ouverte en Sciences de l’Homme et de la Société, ID : 10670/1.u5ar6d
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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.