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Altered miRNA and gene expression in acute myeloid leukemia with complex karyotype identify networks of prognostic relevance

Recently, the p53-miR-34a network has been identified to have an important role in tumorigenesis. As in acute myeloid leukemia with complex karyotype (CK-AML) TP53 alterations are the most common known molecular lesion, we further analyzed the p53-miR-34a axis in a large cohort of CK-AML with known...

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Main Authors: Rücker, Frank Gert (Author) , Russ, A. C. (Author) , Cocciardi, S. (Author) , Kett, H. (Author) , Schlenk, R. F. (Author) , Botzenhardt, U. (Author) , Langer, C. (Author) , Krauter, J. (Author) , Fröhling, S. (Author) , Schlegelberger, B. (Author) , Ganser, A. (Author) , Lichter, Peter (Author) , Zenz, T. (Author) , Döhner, H. (Author) , Döhner, K. (Author) , Bullinger, L. (Author)
Format: Article (Journal)
Language:English
Published: 2013
In: Leukemia
Year: 2013, Volume: 27, Issue: 2, Pages: 353-361
ISSN:1476-5551
DOI:10.1038/leu.2012.208
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/leu.2012.208
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/leu2012208
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Author Notes:F.G. Rücker, A.C. Russ, S. Cocciardi, H. Kett, R.F. Schlenk, U. Botzenhardt, C. Langer, J. Krauter, S. Fröhling, B. Schlegelberger, A. Ganser, P. Lichter, T. Zenz, H. Döhner, K. Döhner and L. Bullinger
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Summary:Recently, the p53-miR-34a network has been identified to have an important role in tumorigenesis. As in acute myeloid leukemia with complex karyotype (CK-AML) TP53 alterations are the most common known molecular lesion, we further analyzed the p53-miR-34a axis in a large cohort of CK-AML with known TP53 status (TP53altered, n=57; TP53unaltered, n=31; altered indicates loss and/or mutation of TP53). Profiling microRNA (miRNA) expression delineated TP53 alteration-associated miRNA profiles, and identified miR-34a and miR-100 as the most significantly down- and upregulated miRNA, respectively. Moreover, we found a distinct miR-34a expression-linked gene expression profile enriched for genes belonging to p53-associated pathways, and implicated in cell cycle progression or apoptosis. Clinically, low miR-34a expression and TP53 alterations predicted for chemotherapy resistance and inferior outcome. Notably, in TP53unaltered CK-AML, high miR-34a expression predicted for inferior overall survival (OS), whereas in TP53biallelic altered CK-AML, high miR-34a expression pointed to better OS. Thus, detailed molecular profiling links impaired p53 to decreased miR-34a expression, but also identifies p53-independent miR-34a induction mechanisms as shown in TP53biallelic altered cell lines treated with 15-deoxy-Δ12,14-prostaglandin. An improved understanding of this mechanism might provide novel therapeutic options to restore miR-34a function and thereby induce cell cycle arrest and apoptosis in TP53altered CK-AML.
Item Description:Advance online publication, 10 August 2012
Gesehen am 24.01.2022
Physical Description:Online Resource
ISSN:1476-5551
DOI:10.1038/leu.2012.208

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