Oncogene- and drug resistance-associated alternative exon usage in acute myeloid leukemia (AML).
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.
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.
Aminetou Mint
AM
Mohamed
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.
Marie
M
Balsat
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.
Morgan
M
Thenoz
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.
Catherine
C
Koering
INSERM, UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Lea
L
Payen-Gay
Jean-Pierre Aubert Center, INSERM U837, Facteurs de Persistance des Cellules Leucémiques, Institute for Cancer Research in Lille, Lille Cedex, France.
Meyling
M
Cheok
Centre de Recherche sur le Cancer de Lyon, Inserm, Epissage Alternatif et Progression Tumorale, Lyon, France.
Hussein
H
Mortada
Centre de Recherche sur le Cancer de Lyon, Inserm, Epissage Alternatif et Progression Tumorale, Lyon, France.
Didier
D
Auboeuf
Centre de Recherche sur le Cancer de Lyon, Inserm, Echappement aux Systèmes de Sauvegarde et Plasticité Cellulaire, Lyon, France.
Christiane
C
Pinatel
Université Lyon I, Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
Mohamed
M
El-Hamri
Centre de Recherche sur le Cancer de Lyon, Inserm, Anticorps Anticancer, Lyon, France.
Charles
C
Dumontet
Centre de Recherche sur le Cancer de Lyon, Inserm, Anticorps Anticancer, Lyon, France.
Emeline
E
Cros
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.|Université de Saint Etienne, Laboratoire d'Hématologie, CHU de Saint-Etienne, Saint Etienne, France.
Pascale
P
Flandrin-Gresta
Centre de Recherche sur le Cancer de Lyon, Inserm, Epissage Alternatif et Progression Tumorale, Lyon, France.
Olivier
O
Nibourel
Centre de Recherche sur le Cancer de Lyon, Inserm, Epissage Alternatif et Progression Tumorale, Lyon, France.
Claude
C
Preudhomme
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.|Université Lyon I, Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
Mauricette
M
Michallet
Université Lyon I, Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
Xavier
X
Thomas
Université Lyon I, Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
Franck
F
Nicolini
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.|Université de Saint Etienne, Laboratoire d'Hématologie, CHU de Saint-Etienne, Saint Etienne, France.
Françoise
F
Solly
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.|Institut de Cancérologie de la Loire, CHU de Saint-Etienne, Saint Priest en Jarez, France.
Denis
D
Guyotat
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.|Université de Saint Etienne, Laboratoire d'Hématologie, CHU de Saint-Etienne, Saint Etienne, France.
Lydia
L
Campos
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.|Université Lyon I, Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
Eric
E
Wattel
Université Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Faculté de Médecine Lyon Sud, ENS - HCL, Pierre Bénite, France.
Franck
F
Mortreux
D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D018943:Anthracyclines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015513:Oncogene Proteins / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D025721:WT1 Proteins / Q000378:metabolism
D018943:Anthracyclines; D000970:Antineoplastic Agents; D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering; D025721:WT1 Proteins; C583751:WT1 protein, human; D003561:Cytarabine; D004317:Doxorubicin; D001374:Azacitidine
DEK; WT1; acute myeloid leukemia; alternative splicing; multidrug resistance