Overexpression and knockout of miR-126 both promote leukemogenesis Journal Article


Authors: Li, Z; Chen, P; Su, R.; Li, Y; Hu, C; Wang, Y; Arnovitz, S; He, M; Gurbuxani, S.; Zuo, Z.; Elkahloun, A. G.; Li, S; Weng, H.; Huang, H; Neilly, M. B.; Wang, S; Olson, E. N.; Larson, R. A.; Le Beau, M. M.; Zhang, J; Jiang, X; Wei, M; Jin, J; Liu, P. P.; Chen, J
Article Title: Overexpression and knockout of miR-126 both promote leukemogenesis
Abstract: It is generally assumed that gain- and loss-of-function manipulations of a functionally important gene should lead to the opposite phenotypes. We show in this study that both overexpression and knockout of microRNA (miR)-126 surprisingly result in enhanced leukemogenesis in cooperation with the t(8;21) fusion genes AML1-ETO/RUNX1-RUNX1T1 and AML1-ETO9a (a potent oncogenic isoform of AML1-ETO). In accordance with our observation that increased expression of miR-126 is associated with unfavorable survival in patients with t(8;21) acute myeloid leukemia (AML), we show that miR-126 overexpression exhibits a stronger effect on long-term survival and progression of AML1-ETO9a-mediated leukemia stem cells/leukemia initiating cells (LSCs/LICs) in mice than does miR-126 knockout. Furthermore, miR-126 knockout substantially enhances responsiveness of leukemia cells to standard chemotherapy. Mechanistically, miR-126 overexpression activates genes that are highly expressed in LSCs/LICs and/or primitive hematopoietic stem/progenitor cells, likely through targeting ERRFI1 and SPRED1, whereas miR-126 knockout activates genes that are highly expressed in committed, more differentiated hematopoietic progenitor cells, presumably through inducing FZD7 expression. Our data demonstrate that miR-126 plays a critical but 2-faceted role in leukemia and thereby uncover a new layer of miRNA regulation in cancer. Moreover, because miR-126 depletion can sensitize AML cells to standard chemotherapy, our data also suggest that miR-126 represents a promising therapeutic target.
Journal Title: Blood
Volume: 126
Issue: 17
ISSN: 1528-0020; 0006-4971
Publisher: American Society of Hematology  
Journal Place: United States
Date Published: 2015
Start Page: 2005
End Page: 2015
Language: eng
DOI/URL:
Notes: LR: 20151104; JID: 7603509; OID: NLM: PMC4616234 [Available on 10/22/16]; PMCR: 2016/10/22 00:00; 2015/04/05 [received]; 2015/09/04 [accepted]; 2015/09/11 [aheadofprint]; ppublish