TY - JOUR
T1 - Distinct microRNA expression profiles in acute myeloid leukemia with common translocations
AU - Li, Zejuan
AU - Lu, Jun
AU - Sun, Miao
AU - Mi, Shuangli
AU - Zhang, Hao
AU - Luo, Roger T.
AU - Chen, Ping
AU - Wang, Yungui
AU - Yan, Ming
AU - Qian, Zhijian
AU - Neilly, Mary Beth
AU - Jin, Jie
AU - Zhang, Yanming
AU - Bohlander, Stefan K.
AU - Zhang, Dong Er
AU - Larson, Richard A.
AU - Le Beau, Michelle M.
AU - Thirman, Michael J.
AU - Golub, Todd R.
AU - Rowley, Janet D.
AU - Chen, Jianjun
PY - 2008/10/7
Y1 - 2008/10/7
N2 - 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.
AB - 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.
KW - Apoptosis and cell viability and proliferation
KW - Core binding factor (CBF)
KW - MicroRNA expression profiling
KW - PLK2
KW - miR-126
UR - http://www.scopus.com/inward/record.url?scp=55749099505&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=55749099505&partnerID=8YFLogxK
U2 - 10.1073/pnas.0808266105
DO - 10.1073/pnas.0808266105
M3 - Article
C2 - 18832181
AN - SCOPUS:55749099505
SN - 0027-8424
VL - 105
SP - 15535
EP - 15540
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 40
ER -