Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host.
Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host.
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DOI：
10.1038/s41586-018-0125-z
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发表时间：
2018-05
期刊：
影响因子：
64.8
通讯作者：
Jabri B
中科院分区：
文献类型：
--
作者：
Meisel M;Hinterleitner R;Pacis A;Chen L;Earley ZM;Mayassi T;Pierre JF;Ernest JD;Galipeau HJ;Thuille N;Bouziat R;Buscarlet M;Ringus DL;Wang Y;Li Y;Dinh V;Kim SM;McDonald BD;Zurenski MA;Musch MW;Furtado GC;Lira SA;Baier G;Chang EB;Eren AM;Weber CR;Busque L;Godley LA;Verdú EF;Barreiro LB;Jabri B
编码表观遗传修饰酶的泰特甲基胞嘧啶双加氧酶2（TET 2）的体细胞突变驱动造血系统恶性肿瘤的发展。在人类和小鼠中，TET 2缺乏导致造血干细胞的自我更新增加，净发育偏向骨髓谱系。然而，白血病前骨髓增生（PMP）仅发生在一部分Tet 2 −/−小鼠和具有TET 2突变的人类中，这表明疾病发作需要外部非细胞自主因素。在这里，我们表明，细菌易位和增加白细胞介素-6的生产，导致小肠屏障功能障碍，是至关重要的PMP在小鼠的发展缺乏Tet 2表达的造血细胞。此外，在无菌Tet 2 −/−小鼠中，PMP可以通过破坏肠道屏障完整性或响应全身细菌刺激（如Toll样受体2激动剂）来诱导。PMP被抗生素治疗逆转，并且未能在无菌Tet 2 −/−小鼠中发展，这说明了微生物信号在这种疾病发展中的重要性。我们的研究结果表明，在PMP的发展中需要微生物依赖性炎症，并为Tet 2 −/−小鼠中观察到的PMP转化率变化提供了机制基础。这项研究将提示新的调查路线，可能会深刻影响造血系统恶性肿瘤的预防和管理。
Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies. In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage. However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2−/− mice and humans with TET2 mutations, suggesting that extrinsic non-cell-autonomous factors are required for disease onset. Here we show that bacterial translocation and increased interleukin-6 production, resulting from dysfunction of the small-intestinal barrier, are critical for the development of PMP in mice that lack Tet2 expression in haematopoietic cells. Furthermore, in symptom-free Tet2−/− mice, PMP can be induced by disrupting intestinal barrier integrity, or in response to systemic bacterial stimuli such as the toll-like receptor 2 agonist. PMP was reversed by antibiotic treatment and failed to develop in germ-free Tet2−/− mice, which illustrates the importance of microbial signals in the development of this condition. Our findings demonstrate the requirement for microbial-dependent inflammation in the development of PMP and provide a mechanistic basis for the variation in PMP penetrance observed in Tet2−/− mice. This study will prompt new lines of investigation that may profoundly affect the prevention and management of haematopoietic malignancies.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
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：
45.3
作者：
Kristinsson, Sigurdur Y.;Bjorkholm, Magnus;Goldin, Lynn R.
通讯作者：
Goldin, Lynn R.
影响因子：
50.3
作者：
Kunimoto H;Meydan C;Nazir A;Whitfield J;Shank K;Rapaport F;Maher R;Pronier E;Meyer SC;Garrett-Bakelman FE;Tallman M;Melnick A;Levine RL;Shih AH
通讯作者：
Shih AH