title: 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.
authors.affiliation: Center of Immunology of Marseille-Luminy, Université de la Méditerranée, Marseille cedex 9, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bonnet
authors.forename: Marie
authors.initials: M
authors.lastname: Loosveld
authors.forename: Bertrand
authors.initials: B
authors.lastname: Montpellier
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Navarro
authors.forename: Benoit
authors.initials: B
authors.lastname: Quilichini
authors.forename: Christophe
authors.initials: C
authors.lastname: Picard
authors.forename: Julie
authors.initials: J
authors.lastname: Di Cristofaro
authors.forename: Claude
authors.initials: C
authors.lastname: Bagnis
authors.forename: Chantal
authors.initials: C
authors.lastname: Fossat
authors.forename: Lucie
authors.initials: L
authors.lastname: Hernandez
authors.forename: Emilie
authors.initials: E
authors.lastname: Mamessier
authors.forename: Sandrine
authors.initials: S
authors.lastname: Roulland
authors.forename: Ester
authors.initials: E
authors.lastname: Morgado
authors.forename: Christine
authors.initials: C
authors.lastname: Formisano-Tréziny
authors.forename: Willem A
authors.initials: WA
authors.lastname: Dik
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.forename: Thomas
authors.initials: T
authors.lastname: Prebet
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Gérard
authors.initials: G
authors.lastname: Michel
authors.forename: Jean
authors.initials: J
authors.lastname: Gabert
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Macintyre
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Dominique
authors.initials: D
authors.lastname: Payet-Bornet
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nadel
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002648:Child; D015973:Gene Expression Regulation, Leukemic; D016259:Genes, myc; D006801:Humans; D019169:Jurkat Cells; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human