The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis

Christiaan J. Stavast; Iris van Zuijen; Elena Karkoulia; Arman Özçelik; Antoinette van Hoven-Beijen; Leticia G. Leon; Jane S.A. Voerman; George M.C. Janssen; Peter A. van Veelen; Monika Burocziova; Rutger W.W. Brouwer; Wilfred F.J. van IJcken; Alex Maas; Eric M. Bindels; Vincent H.J. van der Velden; Christopher Schliehe; Peter D. Katsikis; Meritxell Alberich-Jorda; Stefan J. Erkeland

doi:10.1038/s41375-021-01461-5

The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis

Christiaan J. Stavast, Iris van Zuijen, Elena Karkoulia, Arman Özçelik, Antoinette van Hoven-Beijen, Leticia G. Leon, Jane S.A. Voerman, George M.C. Janssen, Peter A. van Veelen, Monika Burocziova, Rutger W.W. Brouwer, Wilfred F.J. van IJcken, Alex Maas, Eric M. Bindels, Vincent H.J. van der Velden, Christopher Schliehe, Peter D. Katsikis, Meritxell Alberich-Jorda, Stefan J. Erkeland^*

^*Corresponding author for this work

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Abstract

MIR139 is a tumor suppressor and is commonly silenced in acute myeloid leukemia (AML). However, the tumor-suppressing activities of miR-139 and molecular mechanisms of MIR139-silencing remain largely unknown. Here, we studied the poorly prognostic MLL-AF9 fusion protein-expressing AML. We show that MLL-AF9 expression in hematopoietic precursors caused epigenetic silencing of MIR139, whereas overexpression of MIR139 inhibited in vitro and in vivo AML outgrowth. We identified novel miR-139 targets that mediate the tumor-suppressing activities of miR-139 in MLL-AF9 AML. We revealed that two enhancer regions control MIR139 expression and found that the polycomb repressive complex 2 (PRC2) downstream of MLL-AF9 epigenetically silenced MIR139 in AML. Finally, a genome-wide CRISPR-Cas9 knockout screen revealed RNA Polymerase 2 Subunit M (POLR2M) as a novel MIR139-regulatory factor. Our findings elucidate the molecular control of tumor suppressor MIR139 and reveal a role for POLR2M in the MIR139-silencing mechanism, downstream of MLL-AF9 and PRC2 in AML. In addition, we confirmed these findings in human AML cell lines with different oncogenic aberrations, suggesting that this is a more common oncogenic mechanism in AML. Our results may pave the way for new targeted therapy in AML.

Original language	English
Pages (from-to)	687-700
Number of pages	14
Journal	Leukemia
Volume	36
Issue number	3
Early online date	5 Nov 2021
DOIs	https://doi.org/10.1038/s41375-021-01461-5
Publication status	Published - Mar 2022

Bibliographical note

Funding Information: For this work, C.J.S. and I.V.Z. were supported by the Dutch Cancer Foundation (KWF), grant no.: 10948. Furthermore, the Dutch Research Council (NWO) Medium Investment Grant 91116004 (partly financed by ZonMw) to P.A.v.V. also supported the work. Furthermore, we would like to thank Yvette Caljouw, Fabiënne van Opstal, Bernard Stikker and Stijn van den Broek for their technical assistance and Dr. G. Dal Collo and Dr. C. Kiernan for critically reviewing the manuscript. In addition, we would like to acknowledge Dr. R. Delwel and Dr. R. Avelino for their experimental and technical advice.

Publisher Copyright: © 2021, The Author(s).

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The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesisFinal published version, 5.09 MBLicence: CC BY

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Stavast, C. J., van Zuijen, I., Karkoulia, E., Özçelik, A., van Hoven-Beijen, A., Leon, L. G., Voerman, J. S. A., Janssen, G. M. C., van Veelen, P. A., Burocziova, M., Brouwer, R. W. W., van IJcken, W. F. J., Maas, A., Bindels, E. M., van der Velden, V. H. J., Schliehe, C., Katsikis, P. D., Alberich-Jorda, M., & Erkeland, S. J. (2022). The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis. Leukemia, 36(3), 687-700. Advance online publication. https://doi.org/10.1038/s41375-021-01461-5

@article{bc75ae32970149bda531095df3da8fc5,

title = "The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis",

abstract = "MIR139 is a tumor suppressor and is commonly silenced in acute myeloid leukemia (AML). However, the tumor-suppressing activities of miR-139 and molecular mechanisms of MIR139-silencing remain largely unknown. Here, we studied the poorly prognostic MLL-AF9 fusion protein-expressing AML. We show that MLL-AF9 expression in hematopoietic precursors caused epigenetic silencing of MIR139, whereas overexpression of MIR139 inhibited in vitro and in vivo AML outgrowth. We identified novel miR-139 targets that mediate the tumor-suppressing activities of miR-139 in MLL-AF9 AML. We revealed that two enhancer regions control MIR139 expression and found that the polycomb repressive complex 2 (PRC2) downstream of MLL-AF9 epigenetically silenced MIR139 in AML. Finally, a genome-wide CRISPR-Cas9 knockout screen revealed RNA Polymerase 2 Subunit M (POLR2M) as a novel MIR139-regulatory factor. Our findings elucidate the molecular control of tumor suppressor MIR139 and reveal a role for POLR2M in the MIR139-silencing mechanism, downstream of MLL-AF9 and PRC2 in AML. In addition, we confirmed these findings in human AML cell lines with different oncogenic aberrations, suggesting that this is a more common oncogenic mechanism in AML. Our results may pave the way for new targeted therapy in AML.",

author = "Stavast, {Christiaan J.} and {van Zuijen}, Iris and Elena Karkoulia and Arman {\"O}z{\c c}elik and {van Hoven-Beijen}, Antoinette and Leon, {Leticia G.} and Voerman, {Jane S.A.} and Janssen, {George M.C.} and {van Veelen}, {Peter A.} and Monika Burocziova and Brouwer, {Rutger W.W.} and {van IJcken}, {Wilfred F.J.} and Alex Maas and Bindels, {Eric M.} and {van der Velden}, {Vincent H.J.} and Christopher Schliehe and Katsikis, {Peter D.} and Meritxell Alberich-Jorda and Erkeland, {Stefan J.}",

note = "Funding Information: For this work, C.J.S. and I.V.Z. were supported by the Dutch Cancer Foundation (KWF), grant no.: 10948. Furthermore, the Dutch Research Council (NWO) Medium Investment Grant 91116004 (partly financed by ZonMw) to P.A.v.V. also supported the work. Furthermore, we would like to thank Yvette Caljouw, Fabi{\"e}nne van Opstal, Bernard Stikker and Stijn van den Broek for their technical assistance and Dr. G. Dal Collo and Dr. C. Kiernan for critically reviewing the manuscript. In addition, we would like to acknowledge Dr. R. Delwel and Dr. R. Avelino for their experimental and technical advice. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = mar,

doi = "10.1038/s41375-021-01461-5",

language = "English",

volume = "36",

pages = "687--700",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Nature Publishing Group",

number = "3",

}

Stavast, CJ, van Zuijen, I, Karkoulia, E, Özçelik, A, van Hoven-Beijen, A, Leon, LG, Voerman, JSA, Janssen, GMC, van Veelen, PA, Burocziova, M, Brouwer, RWW, van IJcken, WFJ , Maas, A , Bindels, EM , van der Velden, VHJ , Schliehe, C , Katsikis, PD, Alberich-Jorda, M & Erkeland, SJ 2022, 'The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis', Leukemia, vol. 36, no. 3, pp. 687-700. https://doi.org/10.1038/s41375-021-01461-5

TY - JOUR

T1 - The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis

AU - Stavast, Christiaan J.

AU - van Zuijen, Iris

AU - Karkoulia, Elena

AU - Özçelik, Arman

AU - van Hoven-Beijen, Antoinette

AU - Leon, Leticia G.

AU - Voerman, Jane S.A.

AU - Janssen, George M.C.

AU - van Veelen, Peter A.

AU - Burocziova, Monika

AU - Brouwer, Rutger W.W.

AU - van IJcken, Wilfred F.J.

AU - Maas, Alex

AU - Bindels, Eric M.

AU - van der Velden, Vincent H.J.

AU - Schliehe, Christopher

AU - Katsikis, Peter D.

AU - Alberich-Jorda, Meritxell

AU - Erkeland, Stefan J.

N1 - Funding Information: For this work, C.J.S. and I.V.Z. were supported by the Dutch Cancer Foundation (KWF), grant no.: 10948. Furthermore, the Dutch Research Council (NWO) Medium Investment Grant 91116004 (partly financed by ZonMw) to P.A.v.V. also supported the work. Furthermore, we would like to thank Yvette Caljouw, Fabiënne van Opstal, Bernard Stikker and Stijn van den Broek for their technical assistance and Dr. G. Dal Collo and Dr. C. Kiernan for critically reviewing the manuscript. In addition, we would like to acknowledge Dr. R. Delwel and Dr. R. Avelino for their experimental and technical advice. Publisher Copyright: © 2021, The Author(s).

PY - 2022/3

Y1 - 2022/3

N2 - MIR139 is a tumor suppressor and is commonly silenced in acute myeloid leukemia (AML). However, the tumor-suppressing activities of miR-139 and molecular mechanisms of MIR139-silencing remain largely unknown. Here, we studied the poorly prognostic MLL-AF9 fusion protein-expressing AML. We show that MLL-AF9 expression in hematopoietic precursors caused epigenetic silencing of MIR139, whereas overexpression of MIR139 inhibited in vitro and in vivo AML outgrowth. We identified novel miR-139 targets that mediate the tumor-suppressing activities of miR-139 in MLL-AF9 AML. We revealed that two enhancer regions control MIR139 expression and found that the polycomb repressive complex 2 (PRC2) downstream of MLL-AF9 epigenetically silenced MIR139 in AML. Finally, a genome-wide CRISPR-Cas9 knockout screen revealed RNA Polymerase 2 Subunit M (POLR2M) as a novel MIR139-regulatory factor. Our findings elucidate the molecular control of tumor suppressor MIR139 and reveal a role for POLR2M in the MIR139-silencing mechanism, downstream of MLL-AF9 and PRC2 in AML. In addition, we confirmed these findings in human AML cell lines with different oncogenic aberrations, suggesting that this is a more common oncogenic mechanism in AML. Our results may pave the way for new targeted therapy in AML.

AB - MIR139 is a tumor suppressor and is commonly silenced in acute myeloid leukemia (AML). However, the tumor-suppressing activities of miR-139 and molecular mechanisms of MIR139-silencing remain largely unknown. Here, we studied the poorly prognostic MLL-AF9 fusion protein-expressing AML. We show that MLL-AF9 expression in hematopoietic precursors caused epigenetic silencing of MIR139, whereas overexpression of MIR139 inhibited in vitro and in vivo AML outgrowth. We identified novel miR-139 targets that mediate the tumor-suppressing activities of miR-139 in MLL-AF9 AML. We revealed that two enhancer regions control MIR139 expression and found that the polycomb repressive complex 2 (PRC2) downstream of MLL-AF9 epigenetically silenced MIR139 in AML. Finally, a genome-wide CRISPR-Cas9 knockout screen revealed RNA Polymerase 2 Subunit M (POLR2M) as a novel MIR139-regulatory factor. Our findings elucidate the molecular control of tumor suppressor MIR139 and reveal a role for POLR2M in the MIR139-silencing mechanism, downstream of MLL-AF9 and PRC2 in AML. In addition, we confirmed these findings in human AML cell lines with different oncogenic aberrations, suggesting that this is a more common oncogenic mechanism in AML. Our results may pave the way for new targeted therapy in AML.

UR - http://www.scopus.com/inward/record.url?scp=85118669994&partnerID=8YFLogxK

U2 - 10.1038/s41375-021-01461-5

DO - 10.1038/s41375-021-01461-5

M3 - Article

C2 - 34741119

AN - SCOPUS:85118669994

SN - 0887-6924

VL - 36

SP - 687

EP - 700

JO - Leukemia

JF - Leukemia

IS - 3

ER -

The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis

Abstract

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