Overexpression and knockout of miR-126 both promote leukemogenesis

Zejuan Li, Ping Chen, Rui Su, Yuanyuan Li, Chao Hu, Yungui Wang, Stephen Arnovitz, Miao He, Sandeep Gurbuxani, Zhixiang Zuo, Abdel G. Elkahloun, Shenglai Li, Hengyou Weng, Hao Huang, Mary Beth Neilly, Shusheng Wang, Eric N. Olson, Richard A. Larson, Michelle M. Le Beau, Jiwang Zhang & 5 others Xi Jiang, Minjie Wei, Jie Jin, Paul P. Liu, Jianjun Chen

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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 genesAML1-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 exhibitsa stronger effect on long-term survival and progression of AML1-ETO9a-mediated leukemia stem cells/leukemia initiating cells (LSCs/LICs)inmice than does miR-126 knockout. Furthermore, miR-126 knockout substantially enhances responsiveness of leukemia cells tostandard chemotherapy. Mechanistically, miR-126 overexpression activates genes that are highly expressed in LSCs/LICs and/or primitive hematopoietic stem/progenitor cells, likely through targetingERRFI1 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 playsacriticalbut 2-faceted roleinleukemia and there by 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.

Original languageEnglish (US)
Pages (from-to)2005-2015
Number of pages11
JournalBlood
Volume126
Issue number17
DOIs
StatePublished - Oct 22 2015

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MicroRNAs
Leukemia
Hematopoietic Stem Cells
Stem cells
Chemotherapy
Genes
Acute Myeloid Leukemia
Stem Cells
Drug Therapy
Gene Knockout Techniques
Survival
Myeloid Cells
Protein Isoforms
Fusion reactions
Phenotype

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Li, Z., Chen, P., Su, R., Li, Y., Hu, C., Wang, Y., ... Chen, J. (2015). Overexpression and knockout of miR-126 both promote leukemogenesis. Blood, 126(17), 2005-2015. https://doi.org/10.1182/blood-2015-04-639062

Overexpression and knockout of miR-126 both promote leukemogenesis. / Li, Zejuan; Chen, Ping; Su, Rui; Li, Yuanyuan; Hu, Chao; Wang, Yungui; Arnovitz, Stephen; He, Miao; Gurbuxani, Sandeep; Zuo, Zhixiang; Elkahloun, Abdel G.; Li, Shenglai; Weng, Hengyou; Huang, Hao; Neilly, Mary Beth; Wang, Shusheng; Olson, Eric N.; Larson, Richard A.; Le Beau, Michelle M.; Zhang, Jiwang; Jiang, Xi; Wei, Minjie; Jin, Jie; Liu, Paul P.; Chen, Jianjun.

In: Blood, Vol. 126, No. 17, 22.10.2015, p. 2005-2015.

Research output: Contribution to journalArticle

Li, Z, Chen, P, Su, R, Li, Y, Hu, C, Wang, Y, Arnovitz, S, He, M, Gurbuxani, S, Zuo, Z, Elkahloun, AG, Li, S, Weng, H, Huang, H, Neilly, MB, Wang, S, Olson, EN, Larson, RA, Le Beau, MM, Zhang, J, Jiang, X, Wei, M, Jin, J, Liu, PP & Chen, J 2015, 'Overexpression and knockout of miR-126 both promote leukemogenesis', Blood, vol. 126, no. 17, pp. 2005-2015. https://doi.org/10.1182/blood-2015-04-639062
Li Z, Chen P, Su R, Li Y, Hu C, Wang Y et al. Overexpression and knockout of miR-126 both promote leukemogenesis. Blood. 2015 Oct 22;126(17):2005-2015. https://doi.org/10.1182/blood-2015-04-639062
Li, Zejuan ; Chen, Ping ; Su, Rui ; Li, Yuanyuan ; Hu, Chao ; Wang, Yungui ; Arnovitz, Stephen ; He, Miao ; Gurbuxani, Sandeep ; Zuo, Zhixiang ; Elkahloun, Abdel G. ; Li, Shenglai ; Weng, Hengyou ; Huang, Hao ; Neilly, Mary Beth ; Wang, Shusheng ; Olson, Eric N. ; Larson, Richard A. ; Le Beau, Michelle M. ; Zhang, Jiwang ; Jiang, Xi ; Wei, Minjie ; Jin, Jie ; Liu, Paul P. ; Chen, Jianjun. / Overexpression and knockout of miR-126 both promote leukemogenesis. In: Blood. 2015 ; Vol. 126, No. 17. pp. 2005-2015.
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AU - Li, Zejuan

AU - Chen, Ping

AU - Su, Rui

AU - Li, Yuanyuan

AU - Hu, Chao

AU - Wang, Yungui

AU - Arnovitz, Stephen

AU - He, Miao

AU - Gurbuxani, Sandeep

AU - Zuo, Zhixiang

AU - Elkahloun, Abdel G.

AU - Li, Shenglai

AU - Weng, Hengyou

AU - Huang, Hao

AU - Neilly, Mary Beth

AU - Wang, Shusheng

AU - Olson, Eric N.

AU - Larson, Richard A.

AU - Le Beau, Michelle M.

AU - Zhang, Jiwang

AU - Jiang, Xi

AU - Wei, Minjie

AU - Jin, Jie

AU - Liu, Paul P.

AU - Chen, Jianjun

PY - 2015/10/22

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N2 - 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 genesAML1-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 exhibitsa stronger effect on long-term survival and progression of AML1-ETO9a-mediated leukemia stem cells/leukemia initiating cells (LSCs/LICs)inmice than does miR-126 knockout. Furthermore, miR-126 knockout substantially enhances responsiveness of leukemia cells tostandard chemotherapy. Mechanistically, miR-126 overexpression activates genes that are highly expressed in LSCs/LICs and/or primitive hematopoietic stem/progenitor cells, likely through targetingERRFI1 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 playsacriticalbut 2-faceted roleinleukemia and there by 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.

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