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

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.

journal_name

Blood

journal_title

Blood

authors

Bonnet M,Loosveld M,Montpellier B,Navarro JM,Quilichini B,Picard C,Di Cristofaro J,Bagnis C,Fossat C,Hernandez L,Mamessier E,Roulland S,Morgado E,Formisano-Tréziny C,Dik WA,Langerak AW,Prebet T,Vey N,Michel G,Gabert

doi

10.1182/blood-2011-02-336842

subject

Has Abstract

pub_date

2011-06-16 00:00:00

pages

6650-9

issue

24

eissn

0006-4971

issn

1528-0020

pii

blood-2011-02-336842

journal_volume

117

pub_type

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