The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia
Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 over...
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| Format: | Article |
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Springer Nature
2018
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| Online Access: | http://hdl.handle.net/1721.1/116620 https://orcid.org/0000-0001-7168-8672 |
| _version_ | 1826196762329612288 |
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| author | Bassil, Christopher F Ben-Sahra, Issam Benajiba, Lina Alexe, Gabriela Pikman, Yana Conway, Amy S Burgess, Michael R Li, Qing Luciano, Frédéric Auberger, Patrick Galinsky, Ilene DeAngelo, Daniel J Stone, Richard M Zhang, Yi Perkins, Archibald S Shannon, Kevin Puissant, Alexandre Stegmaier, Kimberly Fenouille, Nina Ramos, Azucena Hemann, Michael |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Bassil, Christopher F Ben-Sahra, Issam Benajiba, Lina Alexe, Gabriela Pikman, Yana Conway, Amy S Burgess, Michael R Li, Qing Luciano, Frédéric Auberger, Patrick Galinsky, Ilene DeAngelo, Daniel J Stone, Richard M Zhang, Yi Perkins, Archibald S Shannon, Kevin Puissant, Alexandre Stegmaier, Kimberly Fenouille, Nina Ramos, Azucena Hemann, Michael |
| author_sort | Bassil, Christopher F |
| collection | MIT |
| description | Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens. Keywords: AML; RUNX1; CKMT1; cyclocreatine; arginine metabolism |
| first_indexed | 2024-09-23T10:37:37Z |
| format | Article |
| id | mit-1721.1/116620 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:37:37Z |
| publishDate | 2018 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | mit-1721.1/1166202022-09-30T21:53:26Z The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia Bassil, Christopher F Ben-Sahra, Issam Benajiba, Lina Alexe, Gabriela Pikman, Yana Conway, Amy S Burgess, Michael R Li, Qing Luciano, Frédéric Auberger, Patrick Galinsky, Ilene DeAngelo, Daniel J Stone, Richard M Zhang, Yi Perkins, Archibald S Shannon, Kevin Puissant, Alexandre Stegmaier, Kimberly Fenouille, Nina Ramos, Azucena Hemann, Michael Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Fenouille, Nina Ramos, Azucena Hemann, Michael Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens. Keywords: AML; RUNX1; CKMT1; cyclocreatine; arginine metabolism National Cancer Institute (U.S.) (NIH 1R35 CA210030-01) Stand Up To Cancer Bridge Project National Cancer Institute (U.S.) (David H. Koch Institute for Integrative Cancer Research at MIT. Grant P30-CA14051) 2018-06-26T15:01:12Z 2018-06-26T15:01:12Z 2017-02 2018-06-21T17:15:18Z Article http://purl.org/eprint/type/JournalArticle 1078-8956 1546-170X http://hdl.handle.net/1721.1/116620 Fenouille, Nina, et al. “The Creatine Kinase Pathway Is a Metabolic Vulnerability in EVI1-Positive Acute Myeloid Leukemia.” Nature Medicine, vol. 23, no. 3, Feb. 2017, pp. 301–13. https://orcid.org/0000-0001-7168-8672 http://dx.doi.org/10.1038/NM.4283 Nature Medicine Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Nature PMC |
| spellingShingle | Bassil, Christopher F Ben-Sahra, Issam Benajiba, Lina Alexe, Gabriela Pikman, Yana Conway, Amy S Burgess, Michael R Li, Qing Luciano, Frédéric Auberger, Patrick Galinsky, Ilene DeAngelo, Daniel J Stone, Richard M Zhang, Yi Perkins, Archibald S Shannon, Kevin Puissant, Alexandre Stegmaier, Kimberly Fenouille, Nina Ramos, Azucena Hemann, Michael The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia |
| title | The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia |
| title_full | The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia |
| title_fullStr | The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia |
| title_full_unstemmed | The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia |
| title_short | The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia |
| title_sort | creatine kinase pathway is a metabolic vulnerability in evi1 positive acute myeloid leukemia |
| url | http://hdl.handle.net/1721.1/116620 https://orcid.org/0000-0001-7168-8672 |
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