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

Rücker, F.G.; Russ, A.C.; Cocciardi, S.; Kett, H.; Schlenk, R.F.; Botzenhardt, U.; Langer, C.; Krauter, J.; Fröhling, S.; Schlegelberger, B.; Ganser, A.; Lichter, P.; Zenz, T.; Döhner, H.; Döhner, K.; Bullinger, L.

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

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Item Type:	Article
Title:	Altered miRNA and gene expression in acute myeloid leukemia with complex karyotype identify networks of prognostic relevance
Creators Name:	Rücker, F.G., Russ, A.C., Cocciardi, S., Kett, H., Schlenk, R.F., Botzenhardt, U., Langer, C., Krauter, J., Fröhling, S., Schlegelberger, B., Ganser, A., Lichter, P., Zenz, T., Döhner, H., Döhner, K. and Bullinger, L.
Abstract:	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 (TP53(altered), n=57; TP53(unaltered), 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 TP53(unaltered) CK-AML, high miR-34a expression predicted for inferior overall survival (OS), whereas in TP53(biallelic 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 TP53(biallelic altered) cell lines treated with 15-deoxy-Δ(12,14)-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 TP53(altered) CK-AML.
Keywords:	Acute Myeloid Leukemia, MicroRNA, P53
Source:	Leukemia
ISSN:	1476-5551
Publisher:	Nature Publishing Group
Volume:	27
Number:	2
Page Range:	353-361
Date:	February 2013
Official Publication:	https://doi.org/10.1038/leu.2012.208
PubMed:	View item in PubMed

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