{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:25:25Z","timestamp":1793118325167,"version":"4.5.0"},"reference-count":67,"publisher":"National Academy of Sciences","issue":"8","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National natural science foundation of china","doi-asserted-by":"crossref","award":["32070155"],"award-info":[{"award-number":["32070155"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National natural science foundation of china","doi-asserted-by":"crossref","award":["32270171"],"award-info":[{"award-number":["32270171"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002857","name":"China Pharmaceutical University","doi-asserted-by":"publisher","award":["3154070031"],"award-info":[{"award-number":["3154070031"]}],"id":[{"id":"10.13039\/501100002857","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002857","name":"China Pharmaceutical University","doi-asserted-by":"publisher","award":["3342200014"],"award-info":[{"award-number":["3342200014"]}],"id":[{"id":"10.13039\/501100002857","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,2,25]]},"abstract":"<jats:p>Adult T cell leukemia (ATL) is a highly aggressive T cell malignancy characterized by human T cell leukemia virus type 1 (HTLV-1) infection. ATL has a very poor prognosis and lacks satisfactory treatments; therefore, it is critical to identify potential targets in ATL cells in order to develop effective targeted therapeutics. Here, we report the identification of two oncogenes, AK4 and RHOC, as target genes of miR-455-3p, a tumor-suppressive microRNA in ATL patients. Importantly, AK4 and RHOC are highly expressed in ATL and exhibit oncogenic potentials in vitro and in vivo. Interestingly, transcriptome and metabolome analyses reveal a functional overlap of AK4 and RHOC, including activating oncogenic pathways such as Myc targets and deregulating lipid metabolism such as enhancing the production of sphingomyelin, a tumor-promoting lipid. In particular, compared to other types of T cell malignancy such as T cell acute lymphoblastic leukemia (T-ALL) and cutaneous T cell lymphoma (CTCL), ATL is sensitive to sphingomyelin inhibition and AK4 or RHOC depletion. Altogether, we report a distinct dependency of ATL on AK4 and RHOC oncogenes and an oncometabolite sphingomyelin, which together represent targetable vulnerabilities of ATL that could be exploited for developing effective therapeutics.<\/jats:p>","DOI":"10.1073\/pnas.2416412122","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:36:47Z","timestamp":1740137807000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Identification of AK4 and RHOC as potential oncogenes addicted by adult T cell leukemia"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7245-2829","authenticated-orcid":false,"given":"Benquan","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7939-2080","authenticated-orcid":false,"given":"Jun-ichirou","family":"Yasunaga","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, Faculty of Life Sciences, Kumamoto University","place":["Kumamoto, Japan"]},{"name":"Laboratory of Virus Control, Institute for Life and Medical Sciences, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5018-8432","authenticated-orcid":false,"given":"Yi","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University","place":["Nanjing, 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Infectious Diseases, Faculty of Life Sciences, Kumamoto University","place":["Kumamoto, Japan"]},{"name":"Laboratory of Virus Control, Institute for Life and Medical Sciences, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Laboratory of Virus Control, Institute for Life and Medical Sciences, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8125-4528","authenticated-orcid":false,"given":"Kosuke","family":"Toyoda","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, Faculty of Life Sciences, Kumamoto University","place":["Kumamoto, Japan"]},{"name":"Laboratory of Virus Control, Institute for Life and Medical Sciences, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0473-754X","authenticated-orcid":false,"given":"Masao","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology and Infectious Diseases, Faculty of Life Sciences, Kumamoto University","place":["Kumamoto, Japan"]},{"name":"Laboratory of Virus Control, Institute for Life and Medical Sciences, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2003-7201","authenticated-orcid":false,"given":"Guangyong","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"2299","article-title":"HTLV-1 persistence and the oncogenesis of adult T-cell leukemia\/lymphoma","volume":"141","author":"Bangham C. 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Liu G. Ma Effect of HTLV-1 bZIP factor(HBZ) on microRNA expression profile. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE285524. Deposited 30 December 2024."},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.010800"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.3892\/or.2017.5502"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S235794"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.132.6.3005"},{"key":"e_1_3_4_24_2","unstructured":"B. Liu Identification of AK4 and RHOC as novel oncogenes addicted by adult T-cell leukemia. Sequence Read Archive. https:\/\/www.ncbi.nlm.nih.gov\/sra\/PRJNA1187547. 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