Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.
Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.
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DOI：
10.1038/s41467-023-43697-y
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发表时间：
2023-12-07
影响因子：
16.6
通讯作者：
Agarwal, A.
中科院分区：
文献类型：
--
作者：
McClatchy, J.;Strogantsev, R.;Wolfe, E.;Lin, H. Y.;Mohammadhosseini, M.;Davis, B. A.;Eden, C.;Goldman, D.;Fleming, W. H.;Conley, P.;Wu, G.;Cimmino, L.;Mohammed, H.;Agarwal, A.
克隆性造血（CH）是指单个造血干/祖细胞（HSPC）在更广泛的HSPC中获得选择性优势。当与髓系恶性肿瘤相关基因的体细胞突变相关时，如TET 2介导的不确定潜能的克隆性造血或CHIP，它代表了血液恶性肿瘤和心血管疾病的风险增加。IL 1 β在CHIP患者中升高，但其作用尚不清楚。在此，我们发现在造血细胞特异性缺失Tet 2的CHIP小鼠模型中，IL 1 β促进促炎单核细胞/巨噬细胞的扩增，同时淋巴和红系相关增强子和转录因子结合位点的去甲基化失败。在IL 1 β给药后，野生型HSPC中DNA甲基化显著丢失，这被Tet 2缺陷型HSPC抵抗，因此IL 1 β通过上调与自我更新相关的基因和通过抵抗与终末分化相关的转录因子结合位点的去甲基化来增强Tet 2缺陷型HSPC的自我更新能力。使用老年小鼠模型和人类祖细胞，我们证明了靶向IL 1信号转导可能代表白血病前期疾病的早期干预策略。总之，我们的研究结果表明Tet 2是IL 1 β促进的表观遗传程序的重要介质，以维持造血过程中自我更新和谱系分化之间的良好平衡。血液中TET 2突变细胞的扩增与全因死亡率、白血病和心血管疾病的发生风险增加有关。在这里，作者表明IL 1促进TET 2敲除细胞的克隆扩增，增强它们的自我更新，促进它们的骨髓偏好，并削弱IL 1驱动的淋巴和红细胞调节元件的甲基化损失。
Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1β is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1β promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1β administration, which is resisted by Tet2-deficient HSPCs, and thus IL1β enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1β-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis. The expansion of cells with TET2 mutations within the blood is associated with increased risk for all-cause mortality, development of leukemia and cardiovascular disease. Here authors show IL1 promotes the clonal expansion TET2 knockout cells, enhancing their self-renewal, promoting their myeloid bias and impairing an IL1 driven loss of methylation at lymphoid and erythroid regulatory elements.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
64.8
作者：
Bick AG;Weinstock JS;Nandakumar SK;Fulco CP;Bao EL;Zekavat SM;Szeto MD;Liao X;Leventhal MJ;Nasser J;Chang K;Laurie C;Burugula BB;Gibson CJ;Lin AE;Taub MA;Aguet F;Ardlie K;Mitchell BD;Barnes KC;Moscati A;Fornage M;Redline S;Psaty BM;Silverman EK;Weiss ST;Palmer ND;Vasan RS;Burchard EG;Kardia SLR;He J;Kaplan RC;Smith NL;Arnett DK;Schwartz DA;Correa A;de Andrade M;Guo X;Konkle BA;Custer B;Peralta JM;Gui H;Meyers DA;McGarvey ST;Chen IY;Shoemaker MB;Peyser PA;Broome JG;Gogarten SM;Wang FF;Wong Q;Montasser ME;Daya M;Kenny EE;North KE;Launer LJ;Cade BE;Bis JC;Cho MH;Lasky-Su J;Bowden DW;Cupples LA;Mak ACY;Becker LC;Smith JA;Kelly TN;Aslibekyan S;Heckbert SR;Tiwari HK;Yang IV;Heit JA;Lubitz SA;Johnsen JM;Curran JE;Wenzel SE;Weeks DE;Rao DC;Darbar D;Moon JY;Tracy RP;Buth EJ;Rafaels N;Loos RJF;Durda P;Liu Y;Hou L;Lee J;Kachroo P;Freedman BI;Levy D;Bielak LF;Hixson JE;Floyd JS;Whitsel EA;Ellinor PT;Irvin MR;Fingerlin TE;Raffield LM;Armasu SM;Wheeler MM;Sabino EC;Blangero J;Williams LK;Levy BD;Sheu WH;Roden DM;Boerwinkle E;Manson JE;Mathias RA;Desai P;Taylor KD;Johnson AD;NHLBI Trans-Omics for Precision Medicine Consortium;Auer PL;Kooperberg C;Laurie CC;Blackwell TW;Smith AV;Zhao H;Lange E;Lange L;Rich SS;Rotter JI;Wilson JG;Scheet P;Kitzman JO;Lander ES;Engreitz JM;Ebert BL;Reiner AP;Jaiswal S;Abecasis G;Sankaran VG;Kathiresan S;Natarajan P
通讯作者：
Natarajan P
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
3.7
作者：
Ariki R;Morikawa S;Mabuchi Y;Suzuki S;Nakatake M;Yoshioka K;Hidano S;Nakauchi H;Matsuzaki Y;Nakamura T;Goitsuka R
通讯作者：
Goitsuka R
影响因子：
11.4
作者：
Burns SS;Kumar R;Pasupuleti SK;So K;Zhang C;Kapur R
通讯作者：
Kapur R