miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential

Sara E. Meyer, David E. Muench, Andrew M. Rogers, Tess J. Newkold, Emily Orr, Eric O’Brien, John P. Perentesis, John G. Doench, Ashish Lal, Patrick J. Morris, Craig J. Thomas, Judy Lieberman, Edwina McGlinn, Bruce J. Aronow, Nathan Salomonis, H. Leighton Grimes

Research output: Contribution to journalArticleResearchpeer-review

Abstract

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27 Kip1 ) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27 Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27 Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.

Original languageEnglish
Pages (from-to)2115-2136
Number of pages22
JournalJournal of Experimental Medicine
Volume215
Issue number8
DOIs
Publication statusPublished - 1 Sep 2018

Cite this

Meyer, S. E., Muench, D. E., Rogers, A. M., Newkold, T. J., Orr, E., O’Brien, E., ... Grimes, H. L. (2018). miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential. Journal of Experimental Medicine, 215(8), 2115-2136. https://doi.org/10.1084/jem.20171312
Meyer, Sara E. ; Muench, David E. ; Rogers, Andrew M. ; Newkold, Tess J. ; Orr, Emily ; O’Brien, Eric ; Perentesis, John P. ; Doench, John G. ; Lal, Ashish ; Morris, Patrick J. ; Thomas, Craig J. ; Lieberman, Judy ; McGlinn, Edwina ; Aronow, Bruce J. ; Salomonis, Nathan ; Grimes, H. Leighton. / miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential. In: Journal of Experimental Medicine. 2018 ; Vol. 215, No. 8. pp. 2115-2136.
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abstract = "We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27 Kip1 ) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27 Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27 Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.",
author = "Meyer, {Sara E.} and Muench, {David E.} and Rogers, {Andrew M.} and Newkold, {Tess J.} and Emily Orr and Eric O’Brien and Perentesis, {John P.} and Doench, {John G.} and Ashish Lal and Morris, {Patrick J.} and Thomas, {Craig J.} and Judy Lieberman and Edwina McGlinn and Aronow, {Bruce J.} and Nathan Salomonis and Grimes, {H. Leighton}",
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Meyer, SE, Muench, DE, Rogers, AM, Newkold, TJ, Orr, E, O’Brien, E, Perentesis, JP, Doench, JG, Lal, A, Morris, PJ, Thomas, CJ, Lieberman, J, McGlinn, E, Aronow, BJ, Salomonis, N & Grimes, HL 2018, 'miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential' Journal of Experimental Medicine, vol. 215, no. 8, pp. 2115-2136. https://doi.org/10.1084/jem.20171312

miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential. / Meyer, Sara E.; Muench, David E.; Rogers, Andrew M.; Newkold, Tess J.; Orr, Emily; O’Brien, Eric; Perentesis, John P.; Doench, John G.; Lal, Ashish; Morris, Patrick J.; Thomas, Craig J.; Lieberman, Judy; McGlinn, Edwina; Aronow, Bruce J.; Salomonis, Nathan; Grimes, H. Leighton.

In: Journal of Experimental Medicine, Vol. 215, No. 8, 01.09.2018, p. 2115-2136.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential

AU - Meyer, Sara E.

AU - Muench, David E.

AU - Rogers, Andrew M.

AU - Newkold, Tess J.

AU - Orr, Emily

AU - O’Brien, Eric

AU - Perentesis, John P.

AU - Doench, John G.

AU - Lal, Ashish

AU - Morris, Patrick J.

AU - Thomas, Craig J.

AU - Lieberman, Judy

AU - McGlinn, Edwina

AU - Aronow, Bruce J.

AU - Salomonis, Nathan

AU - Grimes, H. Leighton

PY - 2018/9/1

Y1 - 2018/9/1

N2 - We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27 Kip1 ) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27 Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27 Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.

AB - We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27 Kip1 ) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27 Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27 Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.

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DO - 10.1084/jem.20171312

M3 - Article

VL - 215

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EP - 2136

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

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