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Pan-cancer analyses have revealed that stemness of cancer cells correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct a gain-of-function screen of epigenetic regulators that may influence GSC self-renewal and tumor immunity. The circadian regulator CLOCK emerged as a top hit in enhancing stem-cell self-renewal, which was amplified in about 5% of human GBM cases. CLOCK and its heterodimeric partner BMAL1 enhanced GSC self-renewal and triggered protumor immunity via transcriptional upregulation of OLFML3, a novel chemokine recruiting immune-suppressive microglia into the tumor microenvironment. In GBM models, CLOCK or OLFML3 depletion reduced intratumoral microglia density and extended overall survival. We conclude that the CLOCK\u2013BMAL1 complex contributes to key GBM hallmarks of GSC maintenance and immunosuppression and, together with its downstream target OLFML3, represents new therapeutic targets for this disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Circadian regulator CLOCK drives GSC self-renewal and metabolism and promotes microglia infiltration through direct regulation of a novel microglia-attracting chemokine, OLFML3. CLOCK and\/or OLFML3 may represent novel therapeutic targets for GBM.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 327<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-19-0400","type":"journal-article","created":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T14:05:18Z","timestamp":1578578718000},"page":"371-381","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":211,"title":["Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment"],"prefix":"10.1158","volume":"10","author":[{"given":"Peiwen","family":"Chen","sequence":"first","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hao","family":"Hsu","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Chang","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Tan","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengdao","family":"Lan","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Zhou","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4593-0901","authenticated-orcid":false,"given":"Denise J.","family":"Spring","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick F.","family":"Lang","sequence":"additional","affiliation":[{"name":"2Department of Neurosurgery and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. 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