TY - JOUR
T1 - Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML
AU - Li, Zejuan
AU - Huang, Hao
AU - Li, Yuanyuan
AU - Jiang, Xi
AU - Chen, Ping
AU - Arnovitz, Stephen
AU - Radmacher, Michael D.
AU - Maharry, Kati
AU - Elkahloun, Abdel
AU - Yang, Xinan
AU - He, Chunjiang
AU - He, Miao
AU - Zhang, Zhiyu
AU - Dohner, Konstanze
AU - Neilly, Mary Beth
AU - Price, Colles
AU - Lussier, Yves A.
AU - Zhang, Yanming
AU - Larson, Richard A.
AU - Le Beau, Michelle M.
AU - Caligiuri, Michael A.
AU - Bullinger, Lars
AU - Valk, Peter J.M.
AU - Delwel, Ruud
AU - Lowenberg, Bob
AU - Liu, Paul P.
AU - Marcucci, Guido
AU - Bloomfield, Clara D.
AU - Rowley, Janet D.
AU - Chen, Jianjun
PY - 2012/3/8
Y1 - 2012/3/8
N2 - Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormalAML (CA-AML) patients.We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially.
AB - Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormalAML (CA-AML) patients.We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially.
UR - https://www.scopus.com/pages/publications/84863269138
UR - https://www.scopus.com/pages/publications/84863269138#tab=citedBy
U2 - 10.1182/blood-2011-10-386235
DO - 10.1182/blood-2011-10-386235
M3 - Article
C2 - 22251480
AN - SCOPUS:84863269138
SN - 0006-4971
VL - 119
SP - 2314
EP - 2324
JO - Blood
JF - Blood
IS - 10
ER -