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 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.
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
F G
FG
Rücker
A C
AC
Russ
S
S
Cocciardi
H
H
Kett
R F
RF
Schlenk
U
U
Botzenhardt
C
C
Langer
J
J
Krauter
S
S
Fröhling
B
B
Schlegelberger
A
A
Ganser
P
P
Lichter
T
T
Zenz
H
H
Döhner
K
K
Döhner
L
L
Bullinger
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
D014408:Biomarkers, Tumor; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53