MicroRNA-106b~25 cluster is upregulated in relapsed MLL-rearranged pediatric acute myeloid leukemia
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Lonneke J. Verboon1, Askar Obulkasim1, Jasmijn D.E. de Rooij1, Jenny E. Katsman-Kuipers1, Edwin Sonneveld2, André Baruchel3, Jan Trka4, Dirk Reinhardt5, Rob Pieters6, Jacqueline Cloos7, Gertjan J.L. Kaspers7, Jan-Henning Klusmann8, Christian Michel Zwaan1, Maarten Fornerod1, Marry M. van den Heuvel-Eibrink1,6
1Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital Rotterdam, Rotterdam, The Netherlands
2Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands
3Department of Hematology, Hopital Saint- Louis, Paris, France
4Department of Pediatric Hematology/Oncology, 2nd Medical School, Charles University, Prague, Czech Republic
5Clinic for Pediatrics III, University Hospital Essen, Essen, Germany
6Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
7Paediatric Oncology/Haematology, VU University Medical Centre, Amsterdam, The Netherlands
8Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Marry M. van den Heuvel-Eibrink, email: [email protected]
Keywords: acute myeloid leukemia, MLL, relapse, miR-106b~25
Received: February 28, 2016 Accepted: June 08, 2016 Published: June 24, 2016
The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements.
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