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

Zejuan Li, Hao Huang, Yuanyuan Li, Xi Jiang, Ping Chen, Stephen Arnovitz, Michael D. Radmacher, Kati Maharry, Abdel Elkahloun, Xinan Yang, Chunjiang He, Miao He, Zhiyu Zhang, Konstanze Dohner, Mary Beth Neilly, Colles Price, Yves A Lussier, Yanming Zhang, Richard A. Larson, Michelle M. Le Beau & 10 others Michael A. Caligiuri, Lars Bullinger, Peter J M Valk, Ruud Delwel, Bob Lowenberg, Paul P. Liu, Guido Marcucci, Clara D. Bloomfield, Janet D. Rowley, Jianjun Chen

Research output: Contribution to journalArticle

110 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)2314-2324
Number of pages11
JournalBlood
Volume119
Issue number10
DOIs
StatePublished - Mar 8 2012
Externally publishedYes

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Homeobox Genes
Up-Regulation
Down-Regulation
Genes
Survival
Apoptosis
Acute Myeloid Leukemia
Testing
Cell Proliferation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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

In: Blood, Vol. 119, No. 10, 08.03.2012, p. 2314-2324.

Research output: Contribution to journalArticle

Li, Z, Huang, H, Li, Y, Jiang, X, Chen, P, Arnovitz, S, Radmacher, MD, Maharry, K, Elkahloun, A, Yang, X, He, C, He, M, Zhang, Z, Dohner, K, Neilly, MB, Price, C, Lussier, YA, Zhang, Y, Larson, RA, Le Beau, MM, Caligiuri, MA, Bullinger, L, Valk, PJM, Delwel, R, Lowenberg, B, Liu, PP, Marcucci, G, Bloomfield, CD, Rowley, JD & Chen, J 2012, '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', Blood, vol. 119, no. 10, pp. 2314-2324. https://doi.org/10.1182/blood-2011-10-386235
Li, Zejuan ; Huang, Hao ; Li, Yuanyuan ; Jiang, Xi ; Chen, Ping ; Arnovitz, Stephen ; Radmacher, Michael D. ; Maharry, Kati ; Elkahloun, Abdel ; Yang, Xinan ; He, Chunjiang ; He, Miao ; Zhang, Zhiyu ; Dohner, Konstanze ; Neilly, Mary Beth ; Price, Colles ; Lussier, Yves A ; Zhang, Yanming ; Larson, Richard A. ; Le Beau, Michelle M. ; Caligiuri, Michael A. ; Bullinger, Lars ; Valk, Peter J M ; Delwel, Ruud ; Lowenberg, Bob ; Liu, Paul P. ; Marcucci, Guido ; Bloomfield, Clara D. ; Rowley, Janet D. ; Chen, Jianjun. / 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. In: Blood. 2012 ; Vol. 119, No. 10. pp. 2314-2324.
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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 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.",
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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.

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