Oncotarget

Reviews:

How mRNA is misspliced in acute myelogenous leukemia (AML)?

Aminetou Mint Mohamed _, Morgan Thénoz, Françoise Solly, Marie Balsat, Franck Mortreux and Eric Wattel

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Oncotarget. 2014; 5:9534-9545. https://doi.org/10.18632/oncotarget.2304

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Abstract

Aminetou Mint Mohamed*, Morgan Thénoz*, Françoise Solly, Marie Balsat, Franck Mortreux*, Eric Wattel*

Oncovirologie et Biothérapies, CNRS UMR5239, Faculté de Médecine Lyon Sud, Ecole Normale supérieure de Lyon, Hospices Civils de Lyon, Pierre Bénite, France

* These authors equally contributed

Correspondence to:

Eric Wattel, e-mail: eric.wattel@chu-lyon.fr

Received: July 30, 2014     Accepted: July 31, 2014     Published: November 8, 2014

ABSTRACT

Approximately one-third of expressed genes are misspliced in AML, opening the possibility that additional factors than splicing factor mutations might cause RNA missplicing in these diseases. AML cells harbor a constellation of epigenetic modifications and regularly express large amounts of WT1 transcripts. Histone acetylation/methylation and DNA CpG methylation favor either exon skipping or inclusion, mainly through interfering with RNA Pol II-mediated elongation. This can result either from the binding of various factors on Pol II or alternatively from the recruitment of DNA binding factors that create roadblocks to Pol II-induced elongation. WT1 exhibits pleiotropic effects on mRNA splicing, which mainly result from the binding properties of WT1 via its zinc fingers domains to DNA, RNA, and proteins. Through the repression of the kinase SRPK1, WT1 modifies the splicing of VEGF, which plays important roles in hematopoiesis and angiogenesis. At the protein level, WT1 interacts with the splicing factors U2AF2, WTAP, and RPM4. Therefore, AML cells appear to have acquired numerous properties known to interfere with mRNA splicing. The challenge is now to elucidate these links in order to trigger mRNA splicing at the therapeutic level.


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