Research Papers:

Oncogene- and drug resistance-associated alternative exon usage in acute myeloid leukemia (AML)

Aminetou Mint Mohamed _, Marie Balsat, Morgan Thenoz, Catherine Koering, Lea Payen-Gay, Meyling Cheok, Hussein Mortada, Didier Auboeuf, Christiane Pinatel, Mohamed El-Hamri, Charles Dumontet, Emeline Cros, Pascale Flandrin-Gresta, Olivier Nibourel, Claude Preudhomme, Mauricette Michallet, Xavier Thomas, Franck Nicolini, Françoise Solly, Denis Guyotat, Lydia Campos, Eric Wattel and Franck Mortreux

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Oncotarget. 2016; 7:2889-2909. https://doi.org/10.18632/oncotarget.3898

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Aminetou Mint Mohamed1, Marie Balsat1, Morgan Thenoz1, Catherine Koering1, Lea Payen-Gay2, Meyling Cheok3, Hussein Mortada4, Didier Auboeuf4, Christiane Pinatel5, Mohamed El-Hamri6, Charles Dumontet7, Emeline Cros7, Pascale Flandrin-Gresta1,8, Olivier Nibourel4, Claude Preudhomme4, Mauricette Michallet1,6, Xavier Thomas6, Franck Nicolini6, Françoise Solly1,8, Denis Guyotat1,9, Lydia Campos1,8, Eric Wattel1,6,*, Franck Mortreux1,*

1Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS – HCL, Pierre Bénite, France

2INSERM, UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France

3Jean-Pierre Aubert Center, INSERM U837, Facteurs de persistance des cellules leucémiques, Institute for Cancer Research in Lille, Lille cedex, France

4Centre de Recherche sur le Cancer de Lyon, Inserm, Epissage alternatif et progression tumorale, Lyon, France

5Centre de Recherche sur le Cancer de Lyon, Inserm, Echappement aux systèmes de sauvegarde et plasticité cellulaire, Lyon, France

6Université Lyon I, Service d’Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France

7Centre de Recherche sur le Cancer de Lyon, Inserm, Anticorps anticancer, Lyon, France

8Université de Saint Etienne, Laboratoire d’Hématologie, CHU de Saint-Etienne, Saint-Etienne, France

9Institut de Cancérologie de la Loire, CHU de Saint-Etienne, Saint Priest en Jarez, France

*These authors have contributed equally to this work

Correspondence to:

Eric Wattel, e-mail: [email protected]

Franck Mortreux, e-mail: [email protected]

Keywords: acute myeloid leukemia, alternative splicing, WT1, DEK, multidrug resistance

Received: March 16, 2015     Accepted: April 28, 2015     Published: May 12, 2015


In addition to spliceosome gene mutations, oncogene expression and drug resistance in AML might influence exon expression. We performed exon-array analysis and exon-specific PCR (ESPCR) to identify specific landscapes of exon expression that are associated with DEK and WT1 oncogene expression and the resistance of AML cells to AraC, doxorubicin or azacitidine. Data were obtained for these five conditions through exon-array analysis of 17 cell lines and 24 patient samples and were extended through qESPCR of samples from 152 additional AML cases. More than 70% of AEUs identified by exon-array were technically validated through ESPCR. In vitro, 1,130 to 5,868 exon events distinguished the 5 conditions from their respective controls while in vivo 6,560 and 9,378 events distinguished chemosensitive and chemoresistant AML, respectively, from normal bone marrow. Whatever the cause of this effect, 30 to 80% of mis-spliced mRNAs involved genes unmodified at the whole transcriptional level. These AEUs unmasked new functional pathways that are distinct from those generated by transcriptional deregulation. These results also identified new putative pathways that could help increase the understanding of the effects mediated by DEK or WT1, which may allow the targeting of these pathways to prevent resistance of AML cells to chemotherapeutic agents.

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