An oncogenic enhancer encodes selective selenium dependency in AML.
An oncogenic enhancer encodes selective selenium dependency in AML.
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DOI：
10.1016/j.stem.2022.01.003
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发表时间：
2022-03-03
期刊：
影响因子：
23.9
通讯作者：
Nakada D
中科院分区：
文献类型：
--
作者：
Eagle K;Jiang Y;Shi X;Li M;Obholzer NP;Hu T;Perez MW;Koren JV;Kitano A;Yi JS;Lin CY;Nakada D
Deregulation of transcription is a hallmark of acute myeloid leukemia (AML) that drives oncogenic expression programs and presents opportunities for therapeutic targeting. By integrating comprehensive pan-cancer enhancer landscapes with genetic dependency mapping, we find that AML-enriched enhancers encode for more-selective tumor dependencies. We hypothesized that this approach could identify actionable dependencies downstream of oncogenic driver events and discovered a MYB-regulated AML-enriched enhancer regulating SEPHS2, a key component of the selenoprotein production pathway. Using a combination of patient samples and mouse models we show that this enhancer upregulates SEPHS2, promoting selenoprotein production and antioxidant function required for AML survival. SEPHS2 and other selenoprotein pathway genes are required for AML growth in vitro. SEPHS2 knockout and selenium dietary restriction significantly delay leukemogenesis in vivo with little effect on normal hematopoiesis. These data validate the utility of enhancer mapping in target identification and suggest that selenoprotein production is an actionable target in AML. Eagle et al. combined pan-cancer genetic dependency data with active enhancer landscape and identified SEPHS2 as a highly AML-specific dependency regulated by MYB bound to its enhancer. SEPHS2 regulates selenoprotein production in AML, suppression of which by diet renders AML susceptible to oxidative stress without harming hematopoiesis.
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影响因子：
50.3
作者：
Jones CL;Stevens BM;D'Alessandro A;Reisz JA;Culp-Hill R;Nemkov T;Pei S;Khan N;Adane B;Ye H;Krug A;Reinhold D;Smith C;DeGregori J;Pollyea DA;Jordan CT
通讯作者：
Jordan CT
影响因子：
48
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Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
8.8
作者：
Gundry MC;Brunetti L;Lin A;Mayle AE;Kitano A;Wagner D;Hsu JI;Hoegenauer KA;Rooney CM;Goodell MA;Nakada D
通讯作者：
Nakada D