Activation of a Mir-181-Targeting HOXA-PBX3 Homeobox Gene Signature Is Associated with Adverse Prognosis of Cytogenetically Abnormal Acute Myeloid Leukemia

Abstract 236

Altered expression of microRNAs (miRNAs, a class of small regulatory RNAs) is associated with various types of cancers, including acute myeloid leukemia (AML). We showed previously that increased expression of miR-181a with or without miR-181b was associated with a favorable prognosis for patients with cytogenetically normal AML (CN-AML). However, the prognostic value of miR-181 expression in cytogenetically abnormal AML (CA-AML) remains elusive, even though CA-AML represents the majority of human AML. To investigate the association of expression signatures of miR-181 family members and of their potential target genes with outcome in patients with primary CA-AML, we employed two independent sets of 86 CA-AML patients to investigate the association of expression signatures of miR-181 family members with outcome. We also used four independent sets of 454 CA-AML patients to identify and validate a prognostic signature of miR-181 targets. In addition, we investigated the biological functions of miR-181a/b and target(s) in leukemia cell lines and in a leukemia mouse model. As with CN-AML, we found that both miR-181a and miR-181b expression signatures are significantly (P<.05) associated with favorable overall survival (OS) of patients, but only the miR-181b signature is an independent predictor in multivariable model tests. An overexpressing gene signature of potential targets of miR-181a/b, HOXA7, HOXA9, HOXA11, and PBX 3, derived from a meta-analysis of three independent sets of 183 patients, was an independent predictor of adverse OS, which was confirmed in a validation set of 271 patients. Ectopic expression of miR-181b significantly (P<.05) promoted apoptosis and decreased viability of MONOMAC-6/t(9;11), THP-1/t(9;11), and KOCL-48/t(4;11), and delayed leukemogenesis in our mouse model; such effects could be reversed by forced expression of PBX3. Our data suggest that the silencing of miR-181b and thereby the activation of the four homeobox genes likely contributes to the poor prognosis of adverse CA-AML patients. Thus, restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways in poor prognosis AML patients may provide new strategies to improve outcome substantially.