Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis
Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other ty...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/170596 |
| _version_ | 1811679297168998400 |
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| author | Guo, Mingrui Chan, Tim Hon Man Zhou, Qiling An, Omer Li, Ying Song, Yangyang Tan, Zi Hui Ng, Vanessa Hui En Peramangalam, Philomina Sona Tan, Zhi Qing Cao, Xinang Iwanaga, Eisaku Matsuoka, Masao Ooi, Melissa G. M. Jen, Wei Ying Koh, Liang Piu Chan, Esther Tan, Lip Kun Goh, Yufen Wang, Wilson Koh, Bryan T. H. Chun, Chan Ming Fullwood, Melissa Jane Chng, Wee Joo Osato, Motomi Pulikkan, John Anto Yang, Henry Chen, Leilei Tenen, Daniel G. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Guo, Mingrui Chan, Tim Hon Man Zhou, Qiling An, Omer Li, Ying Song, Yangyang Tan, Zi Hui Ng, Vanessa Hui En Peramangalam, Philomina Sona Tan, Zhi Qing Cao, Xinang Iwanaga, Eisaku Matsuoka, Masao Ooi, Melissa G. M. Jen, Wei Ying Koh, Liang Piu Chan, Esther Tan, Lip Kun Goh, Yufen Wang, Wilson Koh, Bryan T. H. Chun, Chan Ming Fullwood, Melissa Jane Chng, Wee Joo Osato, Motomi Pulikkan, John Anto Yang, Henry Chen, Leilei Tenen, Daniel G. |
| author_sort | Guo, Mingrui |
| collection | NTU |
| description | Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML. |
| first_indexed | 2024-10-01T03:06:55Z |
| format | Journal Article |
| id | ntu-10356/170596 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:06:55Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1705962023-09-25T15:31:54Z Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis Guo, Mingrui Chan, Tim Hon Man Zhou, Qiling An, Omer Li, Ying Song, Yangyang Tan, Zi Hui Ng, Vanessa Hui En Peramangalam, Philomina Sona Tan, Zhi Qing Cao, Xinang Iwanaga, Eisaku Matsuoka, Masao Ooi, Melissa G. M. Jen, Wei Ying Koh, Liang Piu Chan, Esther Tan, Lip Kun Goh, Yufen Wang, Wilson Koh, Bryan T. H. Chun, Chan Ming Fullwood, Melissa Jane Chng, Wee Joo Osato, Motomi Pulikkan, John Anto Yang, Henry Chen, Leilei Tenen, Daniel G. School of Biological Sciences Cancer Science Institute of Singapore Institute of Molecular and Cell Biology, A*STAR Science::Medicine Science::Biological sciences Acute Myeloid Leukemia Core Binding Factor Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML. Published version This work was supported by the Singapore Ministry of Health’s National Medical Research Council (NMRC), the Singapore National Research Foundation, the Singapore Ministry of Education (MOE) under its Research Centres of Excellence initiative, and the National Institutes of Health with following details: Singapore Translational Research Investigator Award, National Institutes of Health grant (P01 HL131477 (D.G.T.), MOE Tier 2 grants (MOE2019 T2-1-083 and MOE2019 T2-2-008), NMRC Clinician Scientist-Individual Research grants (project IDs: MOH 000214 and MOH-001092-00), and the Health and Biomedical Sciences Industry Alignment Fund Pre-Positioning (H20C6a0034) (L.C.), NMRC Open Fund Young Individual Research grant ( MOH OFYIRG20nov-0011) and MOE Research Scholarship Block grant (N 171 000 019 001) (Q.Z.), as well as MOE Tier 3 grant (MOE2014-T3-1-006) (D.G.T. and L.C.). 2023-09-25T00:57:25Z 2023-09-25T00:57:25Z 2023 Journal Article Guo, M., Chan, T. H. M., Zhou, Q., An, O., Li, Y., Song, Y., Tan, Z. H., Ng, V. H. E., Peramangalam, P. S., Tan, Z. Q., Cao, X., Iwanaga, E., Matsuoka, M., Ooi, M. G. M., Jen, W. Y., Koh, L. P., Chan, E., Tan, L. K., Goh, Y., ...Tenen, D. G. (2023). Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis. Blood, 141(25), 3078-3090. https://dx.doi.org/10.1182/blood.2022015830 0006-4971 https://hdl.handle.net/10356/170596 10.1182/blood.2022015830 36796022 2-s2.0-85160255876 25 141 3078 3090 en Blood © 2023 by The American Society of Hematology. All rights reserved. This paper was published in Blood and is made available with permission of The American Society of Hematology. application/pdf |
| spellingShingle | Science::Medicine Science::Biological sciences Acute Myeloid Leukemia Core Binding Factor Guo, Mingrui Chan, Tim Hon Man Zhou, Qiling An, Omer Li, Ying Song, Yangyang Tan, Zi Hui Ng, Vanessa Hui En Peramangalam, Philomina Sona Tan, Zhi Qing Cao, Xinang Iwanaga, Eisaku Matsuoka, Masao Ooi, Melissa G. M. Jen, Wei Ying Koh, Liang Piu Chan, Esther Tan, Lip Kun Goh, Yufen Wang, Wilson Koh, Bryan T. H. Chun, Chan Ming Fullwood, Melissa Jane Chng, Wee Joo Osato, Motomi Pulikkan, John Anto Yang, Henry Chen, Leilei Tenen, Daniel G. Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis |
| title | Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis |
| title_full | Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis |
| title_fullStr | Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis |
| title_full_unstemmed | Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis |
| title_short | Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis |
| title_sort | core binding factor fusion downregulation of adar2 rna editing contributes to aml leukemogenesis |
| topic | Science::Medicine Science::Biological sciences Acute Myeloid Leukemia Core Binding Factor |
| url | https://hdl.handle.net/10356/170596 |
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