Document Detail


Post-transcriptional deregulation of MYC via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia.
MedLine Citation:
PMID:  21527520     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 post-transcriptional 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 post-transcriptional 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.
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 A Dik; Anton W Langerak; Thomas Prebet; Norbert Vey; Gérard Michel; Jean Gabert; Jean Soulier; Elizabeth A Macintyre; Vahid Asnafi; Dominique Payet-Bornet; Bertrand Nadel
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-28
Journal Detail:
Title:  Blood     Volume:  -     ISSN:  1528-0020     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-4-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Center of Immunology of Marseille Luminy, Universite de la Mediterranee, Marseille, France;
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