Distinct microRNA expression profiles in acute myeloid leukemia with common translocations.
MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific miRNAs may play a role in the development of leukemia with these associated genetic rearrangements.
Li
Zejuan
Z
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Lu
Jun
J
Sun
Miao
M
Mi
Shuangli
S
Zhang
Hao
H
Luo
Roger T
RT
Chen
Ping
P
Wang
Yungui
Y
Yan
Ming
M
Qian
Zhijian
Z
Neilly
Mary Beth
MB
Jin
Jie
J
Zhang
Yanming
Y
Bohlander
Stefan K
SK
Zhang
Dong-Er
DE
Larson
Richard A
RA
Le Beau
Michelle M
MM
Thirman
Michael J
MJ
Golub
Todd R
TR
Rowley
Janet D
JD
Chen
Jianjun
J
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D050660:Core Binding Factors / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014178:Translocation, Genetic
D050660:Core Binding Factors; C527111:MIRN126 microRNA, human; D035683:MicroRNAs; C496126:PLK2 protein, human; D017346:Protein Serine-Threonine Kinases