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You are here: Home / Teams / Alternative splicing and tumoral progression - D. Auboeuf / Publications / Oncogene- and drug resistance-associated alternative exon usage in acute myeloid leukemia (AML).

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

Aminetou M 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, Francoise Solly, Denis Guyotat, Lydia Campos, Eric Wattel, and Franck Mortreux (2016)

Oncotarget, 7(3):2889-909.

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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