title: 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.
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.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, IL 60637, USA.
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.forename: Michael D
authors.initials: MD
authors.lastname: Radmacher
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Abdel
authors.initials: A
authors.lastname: Elkahloun
authors.forename: Xinan
authors.initials: X
authors.lastname: Yang
authors.forename: Chunjiang
authors.initials: C
authors.lastname: He
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Konstanze
authors.initials: K
authors.lastname: Dohner
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.forename: Colles
authors.initials: C
authors.lastname: Price
authors.forename: Yves A
authors.initials: YA
authors.lastname: Lussier
authors.forename: Yanming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Bob
authors.initials: B
authors.lastname: Lowenberg
authors.forename: Paul P
authors.initials: PP
authors.lastname: Liu
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Janet D
authors.initials: JD
authors.lastname: Rowley
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C484298:HOXA11 protein, human; C115962:HOXA7 protein, human; D018398:Homeodomain Proteins; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C097899:homeobox protein HOXA9; C090466:proto-oncogene protein Pbx3