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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

2012; Elsevier BV; Volume: 119; Issue: 10 Linguagem: Inglês

10.1182/blood-2011-10-386235

1528-0020

Zejuan Li, Hao Huang, Yuanyuan Li, Xi Jiang, Ping Chen, Stephen Arnovitz, Michael D. Radmacher, Kati Maharry, Abdel G. Elkahloun, Xinan Yang, Chunjiang He, Miao He, Zhiyu Zhang, Konstanze Döhner, Mary Beth Neilly, Colles Price, Yves A. Lussier, Yanming Zhang, Richard A. Larson, Michelle M. Le Beau, Michael A. Caligiuri, Lars Bullinger, Peter J.M. Valk, Ruud Delwel, Bob Löwenberg, Paul Liu, Guido Marcucci, Clara D. Bloomfield, Janet D. Rowley, Jianjun Chen,

MicroRNA in disease regulation

Abstract 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 abnormal AML (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.