Epigenetic drug library screening identified an LSD1 inhibitor to target UTX-deficient cells for differentiation therapy
Epigenetic drug library screening identified an LSD1 inhibitor to target UTX-deficient cells for differentiation therapy
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表观遗传药物库筛选发现了一种 LSD1 抑制剂，可靶向 UTX 缺陷细胞进行分化治疗
DOI：
10.1038/s41392-019-0040-2
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发表时间：
2019-04
影响因子：
39.3
通讯作者：
Liu Yu
中科院分区：
文献类型：
--
作者：
Wu Baohong;Pan Xiangyu;Chen Xuelan;Chen Mei;Shi Kaidou;Xu Jing;Zheng Jianan;Niu Ting;Chen Chong;Shuai Xiao;Liu Yu
UTX（也称为KDM6A）是一种组蛋白3赖氨酸27去甲基化酶，是骨髓增生异常综合征（MDS）和急性髓性白血病（AML）中最常发生突变的表观遗传调控因子之一。最近的研究表明，utx突变通过阻断造血干细胞和祖细胞（HSPCs）的分化来促进MDS和AML。在这里，我们进行了一项表观遗传药物文库筛选，以寻找能够释放由utx缺陷诱导的HSPCs分化阻断的小分子。我们发现，LSD1的选择性抑制剂SP2509特异性地促进了futx -null型HSPCs的分化，而保留了野生型HSPCs。转录组分析显示，utxloss降低了分化相关基因和肿瘤抑制基因的表达，这与它们在HSPC自我更新和白血病发生中的潜在作用有关。相比之下，SP2509处理逆转了utx -null HSPCs中基因表达的这些变化。因此，Utxloss可能通过compass样复合体降低了H3K4甲基化水平，而SP2509抑制LSD1部分逆转了utx缺陷hspc中H3K4甲基化的降低。此外，SP2509在体外和体内促进了futx -null AML细胞的分化，从而延长了这些白血病小鼠的生存期。因此，我们的研究确定了一种新的策略，专门针对Utx缺乏的癌前细胞和恶性细胞进行分化治疗，并为Utx在调节HSPCs和相关疾病中的作用的分子机制提供了见解。
UTX (also known as KDM6A), a histone 3 lysine 27 demethylase, is among the most frequently mutated epigenetic regulators in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Recent studies have suggested thatUTXmutations promote MDS and AML by blocking the differentiation of hematopoietic stem and progenitor cells (HSPCs). Here, we performed an epigenetic drug library screening for small molecules able to release the differentiation block on HSPCs induced byUTXdeficiency. We found that SP2509, a selective inhibitor of LSD1, specifically promoted the differentiation ofUtx-null HSPCs while sparing wild-type HSPCs. Transcriptome profiling showed thatUtxloss reduced the expression of differentiation-related and tumor suppressor genes, correlating with their potential roles in HSPC self-renewal and leukemogenesis. In contrast, SP2509 treatment reversed these changes in gene expression inUtx-null HSPCs. Accordingly,Utxloss decreased H3K4 methylation level probably through the COMPASS-like complex, while LSD1 inhibition by SP2509 partially reversed the reduction of H3K4 methylation inUtx-deficient HSPCs. Further, SP2509 promoted the differentiation ofUtx-null AML cells in vitro and in vivo and, therefore, extended the survival of these leukemic mice. Thus, our study identified a novel strategy to specifically target both premalignant and malignant cells withUtxdeficiency for differentiation therapy and provided insights into the molecular mechanisms underlying the role of Utx in regulating HSPCs and related diseases.
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DOI：
10.1016/b978-0-12-809633-8.20106-4
发表时间：
2020-02
期刊：
--
影响因子：
--
作者：
A. Prjibelski;Anton I. Korobeynikov;Alla L. Lapidus
通讯作者：
A. Prjibelski;Anton I. Korobeynikov;Alla L. Lapidus
影响因子：
10.5
作者：
Chen C;Liu Y;Lu C;Cross JR;Morris JP 4th;Shroff AS;Ward PS;Bradner JE;Thompson C;Lowe SW
通讯作者：
Lowe SW
DOI：
10.1017/s1359135514000311
发表时间：
2014-03
期刊：
Architectural Research Quarterly
影响因子：
--
作者：
Reihe Ökonomie
通讯作者：
Reihe Ökonomie
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
5.7
作者：
Pishas KI;Drenberg CD;Taslim C;Theisen ER;Johnson KM;Saund RS;Pop IL;Crompton BD;Lawlor ER;Tirode F;Mora J;Delattre O;Beckerle MC;Callen DF;Sharma S;Lessnick SL
通讯作者：
Lessnick SL