Journal
BLOOD
Volume 119, Issue 10, Pages 2314-2324Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-10-386235
Keywords
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Funding
- Leukemia & Lymphoma Society
- CALGB [20801]
- National Institutes of Health [CA127277, P01 CA40046, P30 CA014599]
- American Cancer Society
- Gabrielle's Angel Foundation for Cancer Research
- Spastic Paralysis Foundation of the Illinois, Eastern Iowa Branch of Kiwanis International
- Fidelity Foundation
- U10 of the CALGB LCSC committee [U10 CA101140]
- P50 of OSU Leukemia SPORE [P50CA140158]
- Leukemia Clinical Research Foundation
- National Human Genome Research Institute, National Institutes of Health
- National Natural Science Foundation of China [60971099]
- Deutsche Jose Carreras Leukamie Stiftung [R 06/41v]
- Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium) [BU 1339/3-1]
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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. (Blood. 2012;119(10):2314-2324)
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