Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation
Epigenetic gene regulation and metabolism are highly intertwined, yet little is known about whether altered epigenetics influence cellular metabolism during cancer progression. Here, we show that EZH2 and NRAS mutations cooperatively induce progression of myeloproliferative neoplasms to highly penet...
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| Veröffentlicht in: | Cancer discovery 2019-09, Vol.9 (9), p.1228-1247 |
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| creator | Gu, Zhimin Liu, Yuxuan Cai, Feng Patrick, McKenzie Zmajkovic, Jakub Cao, Hui Zhang, Yuannyu Tasdogan, Alpaslan Chen, Mingyi Qi, Le Liu, Xin Li, Kailong Lyu, Junhua Dickerson, Kathryn E Chen, Weina Ni, Min Merritt, Matthew E Morrison, Sean J Skoda, Radek C DeBerardinis, Ralph J Xu, Jian |
| description | Epigenetic gene regulation and metabolism are highly intertwined, yet little is known about whether altered epigenetics influence cellular metabolism during cancer progression. Here, we show that EZH2 and NRAS
mutations cooperatively induce progression of myeloproliferative neoplasms to highly penetrant, transplantable, and lethal myeloid leukemias in mice. EZH1, an EZH2 homolog, is indispensable for EZH2-deficient leukemia-initiating cells and constitutes an epigenetic vulnerability. BCAT1, which catalyzes the reversible transamination of branched-chain amino acids (BCAA), is repressed by EZH2 in normal hematopoiesis and aberrantly activated in EZH2-deficient myeloid neoplasms in mice and humans. BCAT1 reactivation cooperates with NRAS
to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling in EZH2-deficient leukemia cells. Genetic and pharmacologic inhibition of BCAT1 selectively impairs EZH2-deficient leukemia-initiating cells and constitutes a metabolic vulnerability. Hence, epigenetic alterations rewire intracellular metabolism during leukemic transformation, causing epigenetic and metabolic vulnerabilities in cancer-initiating cells. SIGNIFICANCE: EZH2 inactivation and oncogenic NRAS cooperate to induce leukemic transformation of myeloproliferative neoplasms by activating BCAT1 to enhance BCAA metabolism and mTOR signaling. We uncover a mechanism by which epigenetic alterations rewire metabolism during cancer progression, causing epigenetic and metabolic liabilities in cancer-initiating cells that may be exploited as potential therapeutics.
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| doi_str_mv | 10.1158/2159-8290.cd-19-0152 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6726547</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>31189531</sourcerecordid><originalsourceid>FETCH-LOGICAL-c525t-9a321db1bbe89095b7c60d5471dfefa15809680d9ccda9b29fe89fcb7d52ae7a3</originalsourceid><addsrcrecordid>eNpVkG9LwzAQxoMobsx9A5F8gc4kbdrmjTC7zQkVQeYb34T8ndW1GUk38NvbMi16b-64u-c57gfANUYzjGl-SzBlUU4YmikdYRYhTMkZGA_t86HOkhGYhvCBukhYQlF2CUYxxjmjMR6DdelCgM7C5duawBez927rRR3gfTGfwyfTCul2Vahh6-DCV0cDS3P4NHWl4MaLJljna9FWrrkCF1bsgpn-5Al4XS03xToqnx8ei3kZKUpoGzERE6wlltLkDDEqM5UiTZMMa2us6H5DLM2RZkppwSRhttuzSmaaEmEyEU_A3cl3f5C10co0rRc7vvdVLfwXd6Li_ydN9c637sjTjKTdnc4gORko373ujR20GPEeLu_J8Z4iLxYcM97D7WQ3f-8Ool-U8Te0w3ay</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>American Association for Cancer Research</source><creator>Gu, Zhimin ; Liu, Yuxuan ; Cai, Feng ; Patrick, McKenzie ; Zmajkovic, Jakub ; Cao, Hui ; Zhang, Yuannyu ; Tasdogan, Alpaslan ; Chen, Mingyi ; Qi, Le ; Liu, Xin ; Li, Kailong ; Lyu, Junhua ; Dickerson, Kathryn E ; Chen, Weina ; Ni, Min ; Merritt, Matthew E ; Morrison, Sean J ; Skoda, Radek C ; DeBerardinis, Ralph J ; Xu, Jian</creator><creatorcontrib>Gu, Zhimin ; Liu, Yuxuan ; Cai, Feng ; Patrick, McKenzie ; Zmajkovic, Jakub ; Cao, Hui ; Zhang, Yuannyu ; Tasdogan, Alpaslan ; Chen, Mingyi ; Qi, Le ; Liu, Xin ; Li, Kailong ; Lyu, Junhua ; Dickerson, Kathryn E ; Chen, Weina ; Ni, Min ; Merritt, Matthew E ; Morrison, Sean J ; Skoda, Radek C ; DeBerardinis, Ralph J ; Xu, Jian</creatorcontrib><description>Epigenetic gene regulation and metabolism are highly intertwined, yet little is known about whether altered epigenetics influence cellular metabolism during cancer progression. Here, we show that EZH2 and NRAS
mutations cooperatively induce progression of myeloproliferative neoplasms to highly penetrant, transplantable, and lethal myeloid leukemias in mice. EZH1, an EZH2 homolog, is indispensable for EZH2-deficient leukemia-initiating cells and constitutes an epigenetic vulnerability. BCAT1, which catalyzes the reversible transamination of branched-chain amino acids (BCAA), is repressed by EZH2 in normal hematopoiesis and aberrantly activated in EZH2-deficient myeloid neoplasms in mice and humans. BCAT1 reactivation cooperates with NRAS
to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling in EZH2-deficient leukemia cells. Genetic and pharmacologic inhibition of BCAT1 selectively impairs EZH2-deficient leukemia-initiating cells and constitutes a metabolic vulnerability. Hence, epigenetic alterations rewire intracellular metabolism during leukemic transformation, causing epigenetic and metabolic vulnerabilities in cancer-initiating cells. SIGNIFICANCE: EZH2 inactivation and oncogenic NRAS cooperate to induce leukemic transformation of myeloproliferative neoplasms by activating BCAT1 to enhance BCAA metabolism and mTOR signaling. We uncover a mechanism by which epigenetic alterations rewire metabolism during cancer progression, causing epigenetic and metabolic liabilities in cancer-initiating cells that may be exploited as potential therapeutics.
.
.</description><identifier>ISSN: 2159-8274</identifier><identifier>EISSN: 2159-8290</identifier><identifier>DOI: 10.1158/2159-8290.cd-19-0152</identifier><identifier>PMID: 31189531</identifier><language>eng</language><publisher>United States</publisher><subject>Amino Acids, Branched-Chain - metabolism ; Animals ; Enhancer of Zeste Homolog 2 Protein - genetics ; Enhancer of Zeste Homolog 2 Protein - metabolism ; GTP Phosphohydrolases - genetics ; Humans ; Leukemia - genetics ; Leukemia - metabolism ; Leukemia - pathology ; Membrane Proteins - genetics ; Mice ; Mutation ; Myeloproliferative Disorders - complications ; Myeloproliferative Disorders - genetics ; Myeloproliferative Disorders - metabolism ; Neoplasm Transplantation ; Signal Transduction ; TOR Serine-Threonine Kinases - metabolism ; Transaminases - metabolism</subject><ispartof>Cancer discovery, 2019-09, Vol.9 (9), p.1228-1247</ispartof><rights>2019 American Association for Cancer Research.</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c525t-9a321db1bbe89095b7c60d5471dfefa15809680d9ccda9b29fe89fcb7d52ae7a3</citedby><cites>FETCH-LOGICAL-c525t-9a321db1bbe89095b7c60d5471dfefa15809680d9ccda9b29fe89fcb7d52ae7a3</cites><orcidid>0000-0003-4617-9651 ; 0000-0003-1220-2243 ; 0000-0003-1988-7337</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31189531$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gu, Zhimin</creatorcontrib><creatorcontrib>Liu, Yuxuan</creatorcontrib><creatorcontrib>Cai, Feng</creatorcontrib><creatorcontrib>Patrick, McKenzie</creatorcontrib><creatorcontrib>Zmajkovic, Jakub</creatorcontrib><creatorcontrib>Cao, Hui</creatorcontrib><creatorcontrib>Zhang, Yuannyu</creatorcontrib><creatorcontrib>Tasdogan, Alpaslan</creatorcontrib><creatorcontrib>Chen, Mingyi</creatorcontrib><creatorcontrib>Qi, Le</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><creatorcontrib>Li, Kailong</creatorcontrib><creatorcontrib>Lyu, Junhua</creatorcontrib><creatorcontrib>Dickerson, Kathryn E</creatorcontrib><creatorcontrib>Chen, Weina</creatorcontrib><creatorcontrib>Ni, Min</creatorcontrib><creatorcontrib>Merritt, Matthew E</creatorcontrib><creatorcontrib>Morrison, Sean J</creatorcontrib><creatorcontrib>Skoda, Radek C</creatorcontrib><creatorcontrib>DeBerardinis, Ralph J</creatorcontrib><creatorcontrib>Xu, Jian</creatorcontrib><title>Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation</title><title>Cancer discovery</title><addtitle>Cancer Discov</addtitle><description>Epigenetic gene regulation and metabolism are highly intertwined, yet little is known about whether altered epigenetics influence cellular metabolism during cancer progression. Here, we show that EZH2 and NRAS
mutations cooperatively induce progression of myeloproliferative neoplasms to highly penetrant, transplantable, and lethal myeloid leukemias in mice. EZH1, an EZH2 homolog, is indispensable for EZH2-deficient leukemia-initiating cells and constitutes an epigenetic vulnerability. BCAT1, which catalyzes the reversible transamination of branched-chain amino acids (BCAA), is repressed by EZH2 in normal hematopoiesis and aberrantly activated in EZH2-deficient myeloid neoplasms in mice and humans. BCAT1 reactivation cooperates with NRAS
to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling in EZH2-deficient leukemia cells. Genetic and pharmacologic inhibition of BCAT1 selectively impairs EZH2-deficient leukemia-initiating cells and constitutes a metabolic vulnerability. Hence, epigenetic alterations rewire intracellular metabolism during leukemic transformation, causing epigenetic and metabolic vulnerabilities in cancer-initiating cells. SIGNIFICANCE: EZH2 inactivation and oncogenic NRAS cooperate to induce leukemic transformation of myeloproliferative neoplasms by activating BCAT1 to enhance BCAA metabolism and mTOR signaling. We uncover a mechanism by which epigenetic alterations rewire metabolism during cancer progression, causing epigenetic and metabolic liabilities in cancer-initiating cells that may be exploited as potential therapeutics.
.
.</description><subject>Amino Acids, Branched-Chain - metabolism</subject><subject>Animals</subject><subject>Enhancer of Zeste Homolog 2 Protein - genetics</subject><subject>Enhancer of Zeste Homolog 2 Protein - metabolism</subject><subject>GTP Phosphohydrolases - genetics</subject><subject>Humans</subject><subject>Leukemia - genetics</subject><subject>Leukemia - metabolism</subject><subject>Leukemia - pathology</subject><subject>Membrane Proteins - genetics</subject><subject>Mice</subject><subject>Mutation</subject><subject>Myeloproliferative Disorders - complications</subject><subject>Myeloproliferative Disorders - genetics</subject><subject>Myeloproliferative Disorders - metabolism</subject><subject>Neoplasm Transplantation</subject><subject>Signal Transduction</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Transaminases - metabolism</subject><issn>2159-8274</issn><issn>2159-8290</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkG9LwzAQxoMobsx9A5F8gc4kbdrmjTC7zQkVQeYb34T8ndW1GUk38NvbMi16b-64u-c57gfANUYzjGl-SzBlUU4YmikdYRYhTMkZGA_t86HOkhGYhvCBukhYQlF2CUYxxjmjMR6DdelCgM7C5duawBez927rRR3gfTGfwyfTCul2Vahh6-DCV0cDS3P4NHWl4MaLJljna9FWrrkCF1bsgpn-5Al4XS03xToqnx8ei3kZKUpoGzERE6wlltLkDDEqM5UiTZMMa2us6H5DLM2RZkppwSRhttuzSmaaEmEyEU_A3cl3f5C10co0rRc7vvdVLfwXd6Li_ydN9c637sjTjKTdnc4gORko373ujR20GPEeLu_J8Z4iLxYcM97D7WQ3f-8Ool-U8Te0w3ay</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>Gu, Zhimin</creator><creator>Liu, Yuxuan</creator><creator>Cai, Feng</creator><creator>Patrick, McKenzie</creator><creator>Zmajkovic, Jakub</creator><creator>Cao, Hui</creator><creator>Zhang, Yuannyu</creator><creator>Tasdogan, Alpaslan</creator><creator>Chen, Mingyi</creator><creator>Qi, Le</creator><creator>Liu, Xin</creator><creator>Li, Kailong</creator><creator>Lyu, Junhua</creator><creator>Dickerson, Kathryn E</creator><creator>Chen, Weina</creator><creator>Ni, Min</creator><creator>Merritt, Matthew E</creator><creator>Morrison, Sean J</creator><creator>Skoda, Radek C</creator><creator>DeBerardinis, Ralph J</creator><creator>Xu, Jian</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4617-9651</orcidid><orcidid>https://orcid.org/0000-0003-1220-2243</orcidid><orcidid>https://orcid.org/0000-0003-1988-7337</orcidid></search><sort><creationdate>20190901</creationdate><title>Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation</title><author>Gu, Zhimin ; Liu, Yuxuan ; Cai, Feng ; Patrick, McKenzie ; Zmajkovic, Jakub ; Cao, Hui ; Zhang, Yuannyu ; Tasdogan, Alpaslan ; Chen, Mingyi ; Qi, Le ; Liu, Xin ; Li, Kailong ; Lyu, Junhua ; Dickerson, Kathryn E ; Chen, Weina ; Ni, Min ; Merritt, Matthew E ; Morrison, Sean J ; Skoda, Radek C ; DeBerardinis, Ralph J ; Xu, Jian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c525t-9a321db1bbe89095b7c60d5471dfefa15809680d9ccda9b29fe89fcb7d52ae7a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Amino Acids, Branched-Chain - metabolism</topic><topic>Animals</topic><topic>Enhancer of Zeste Homolog 2 Protein - genetics</topic><topic>Enhancer of Zeste Homolog 2 Protein - metabolism</topic><topic>GTP Phosphohydrolases - genetics</topic><topic>Humans</topic><topic>Leukemia - genetics</topic><topic>Leukemia - metabolism</topic><topic>Leukemia - pathology</topic><topic>Membrane Proteins - genetics</topic><topic>Mice</topic><topic>Mutation</topic><topic>Myeloproliferative Disorders - complications</topic><topic>Myeloproliferative Disorders - genetics</topic><topic>Myeloproliferative Disorders - metabolism</topic><topic>Neoplasm Transplantation</topic><topic>Signal Transduction</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Transaminases - metabolism</topic><toplevel>online_resources</toplevel><creatorcontrib>Gu, Zhimin</creatorcontrib><creatorcontrib>Liu, Yuxuan</creatorcontrib><creatorcontrib>Cai, Feng</creatorcontrib><creatorcontrib>Patrick, McKenzie</creatorcontrib><creatorcontrib>Zmajkovic, Jakub</creatorcontrib><creatorcontrib>Cao, Hui</creatorcontrib><creatorcontrib>Zhang, Yuannyu</creatorcontrib><creatorcontrib>Tasdogan, Alpaslan</creatorcontrib><creatorcontrib>Chen, Mingyi</creatorcontrib><creatorcontrib>Qi, Le</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><creatorcontrib>Li, Kailong</creatorcontrib><creatorcontrib>Lyu, Junhua</creatorcontrib><creatorcontrib>Dickerson, Kathryn E</creatorcontrib><creatorcontrib>Chen, Weina</creatorcontrib><creatorcontrib>Ni, Min</creatorcontrib><creatorcontrib>Merritt, Matthew E</creatorcontrib><creatorcontrib>Morrison, Sean J</creatorcontrib><creatorcontrib>Skoda, Radek C</creatorcontrib><creatorcontrib>DeBerardinis, Ralph J</creatorcontrib><creatorcontrib>Xu, Jian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer discovery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gu, Zhimin</au><au>Liu, Yuxuan</au><au>Cai, Feng</au><au>Patrick, McKenzie</au><au>Zmajkovic, Jakub</au><au>Cao, Hui</au><au>Zhang, Yuannyu</au><au>Tasdogan, Alpaslan</au><au>Chen, Mingyi</au><au>Qi, Le</au><au>Liu, Xin</au><au>Li, Kailong</au><au>Lyu, Junhua</au><au>Dickerson, Kathryn E</au><au>Chen, Weina</au><au>Ni, Min</au><au>Merritt, Matthew E</au><au>Morrison, Sean J</au><au>Skoda, Radek C</au><au>DeBerardinis, Ralph J</au><au>Xu, Jian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation</atitle><jtitle>Cancer discovery</jtitle><addtitle>Cancer Discov</addtitle><date>2019-09-01</date><risdate>2019</risdate><volume>9</volume><issue>9</issue><spage>1228</spage><epage>1247</epage><pages>1228-1247</pages><issn>2159-8274</issn><eissn>2159-8290</eissn><abstract>Epigenetic gene regulation and metabolism are highly intertwined, yet little is known about whether altered epigenetics influence cellular metabolism during cancer progression. Here, we show that EZH2 and NRAS
mutations cooperatively induce progression of myeloproliferative neoplasms to highly penetrant, transplantable, and lethal myeloid leukemias in mice. EZH1, an EZH2 homolog, is indispensable for EZH2-deficient leukemia-initiating cells and constitutes an epigenetic vulnerability. BCAT1, which catalyzes the reversible transamination of branched-chain amino acids (BCAA), is repressed by EZH2 in normal hematopoiesis and aberrantly activated in EZH2-deficient myeloid neoplasms in mice and humans. BCAT1 reactivation cooperates with NRAS
to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling in EZH2-deficient leukemia cells. Genetic and pharmacologic inhibition of BCAT1 selectively impairs EZH2-deficient leukemia-initiating cells and constitutes a metabolic vulnerability. Hence, epigenetic alterations rewire intracellular metabolism during leukemic transformation, causing epigenetic and metabolic vulnerabilities in cancer-initiating cells. SIGNIFICANCE: EZH2 inactivation and oncogenic NRAS cooperate to induce leukemic transformation of myeloproliferative neoplasms by activating BCAT1 to enhance BCAA metabolism and mTOR signaling. We uncover a mechanism by which epigenetic alterations rewire metabolism during cancer progression, causing epigenetic and metabolic liabilities in cancer-initiating cells that may be exploited as potential therapeutics.
.
.</abstract><cop>United States</cop><pmid>31189531</pmid><doi>10.1158/2159-8290.cd-19-0152</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0003-4617-9651</orcidid><orcidid>https://orcid.org/0000-0003-1220-2243</orcidid><orcidid>https://orcid.org/0000-0003-1988-7337</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acids, Branched-Chain - metabolism Animals Enhancer of Zeste Homolog 2 Protein - genetics Enhancer of Zeste Homolog 2 Protein - metabolism GTP Phosphohydrolases - genetics Humans Leukemia - genetics Leukemia - metabolism Leukemia - pathology Membrane Proteins - genetics Mice Mutation Myeloproliferative Disorders - complications Myeloproliferative Disorders - genetics Myeloproliferative Disorders - metabolism Neoplasm Transplantation Signal Transduction TOR Serine-Threonine Kinases - metabolism Transaminases - metabolism |
| title | Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation |
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