Posttranscriptional deregulation of MYC via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia.
Mélanie Bonnet
(1)
,
Marie Loosveld
(2)
,
Bertrand Montpellier
(1)
,
Jean-Marc Navarro
(1)
,
Benoit Quilichini
(2)
,
Christophe Picard
(3, 4)
,
Julie Di Cristofaro
(3)
,
Claude Bagnis
(3, 5)
,
Chantal Fossat
(2)
,
Lucie Hernandez
(6)
,
Emilie Mamessier
(1)
,
Sandrine Roulland
(1)
,
Ester Morgado
(1)
,
Christine Formisano-Tréziny
(4)
,
Willem A Dik
(7)
,
Anton W Langerak
(7)
,
Thomas Prebet
(8)
,
Norbert Vey
(9)
,
Gérard Michel
(2)
,
Jean Gabert
(4)
,
Jean Soulier
(6)
,
Elizabeth A Macintyre
(10, 11)
,
Vahid Asnafi
(12)
,
Dominique Payet-Bornet
(1)
,
Bertrand Nadel
(1)
1
CIML -
Centre d'Immunologie de Marseille - Luminy
2 TIMONE - Hôpital de la Timone [CHU - APHM]
3 ADES - Anthropologie bio-culturelle, Droit, Ethique et Santé
4 IJRBIC - Institut Jean Roche - Biologie des interactions cellulaires
5 Département de thérapie cellulaire et génique
6 3UMR728 INSERM Unité d'immuno-hématologie (UIH) and laboratoire d'hématologie, Hôpital St-Louis, AP-HP
7 Erasmus MC - Erasmus University Medical Center [Rotterdam]
8 Service d'hématologie [Hôpital Edouard Herriot - HCL]
9 Hematology (IPC-Marseille)
10 CHRI - Cytokines, hématopoïèse et réponse immune
11 IRNEM - IFR Necker-Enfants Malades
12 UPD5 - Université Paris Descartes - Paris 5
2 TIMONE - Hôpital de la Timone [CHU - APHM]
3 ADES - Anthropologie bio-culturelle, Droit, Ethique et Santé
4 IJRBIC - Institut Jean Roche - Biologie des interactions cellulaires
5 Département de thérapie cellulaire et génique
6 3UMR728 INSERM Unité d'immuno-hématologie (UIH) and laboratoire d'hématologie, Hôpital St-Louis, AP-HP
7 Erasmus MC - Erasmus University Medical Center [Rotterdam]
8 Service d'hématologie [Hôpital Edouard Herriot - HCL]
9 Hematology (IPC-Marseille)
10 CHRI - Cytokines, hématopoïèse et réponse immune
11 IRNEM - IFR Necker-Enfants Malades
12 UPD5 - Université Paris Descartes - Paris 5
Marie Loosveld
- Fonction : Auteur
- PersonId : 764617
- ORCID : 0000-0002-8372-4148
Christophe Picard
- Fonction : Auteur
- PersonId : 773782
- ORCID : 0000-0001-9118-5239
Julie Di Cristofaro
- Fonction : Auteur
- PersonId : 764618
- ORCID : 0000-0001-7867-6455
Emilie Mamessier
- Fonction : Auteur
- PersonId : 11337
- IdHAL : emilie-mamessier
- ORCID : 0000-0002-3516-0093
- IdRef : 110823478
Sandrine Roulland
- Fonction : Auteur
- PersonId : 176408
- IdHAL : sandrine-roulland
- ORCID : 0000-0003-2187-1959
- IdRef : 083611061
Norbert Vey
- Fonction : Auteur
- PersonId : 762211
- ORCID : 0000-0001-7027-040X
Dominique Payet-Bornet
- Fonction : Auteur
- PersonId : 741466
- IdHAL : dominique-payet
- ORCID : 0000-0003-3196-3814
- IdRef : 161208843
Résumé
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.