Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway.
Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway.
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DOI：
10.1172/jci.insight.163864
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发表时间：
2023-05-08
期刊：
影响因子：
8
通讯作者：
Kapur, Reuben
中科院分区：
文献类型：
--
作者：
Palam, Lakshmi Reddy;Ramdas, Baskar;Pickerell, Katelyn;Pasupuleti, Santhosh Kumar;Kanumuri, Rahul;Cesarano, Annamaria;Szymanski, Megan;Selman, Bryce;Dave, Utpal P.;Sandusky, George;Perna, Fabiana;Paczesny, Sophie;Kapur, Reuben
DNA甲基转移酶3A（DNMT3A）的功能缺失突变在大量细胞遗传学正常的急性髓系白血病（AML）患者中可见，且常与预后不良相关。DNMT3A突变是白血病前期的早期事件，与其他基因损伤共同作用时，会引发全面的白血病。在此，我们发现造血干细胞和祖细胞（HSC/Ps）中Dnmt3a的缺失会导致骨髓增殖，这与磷脂酰肌醇3 - 激酶（PI3K）通路的过度激活有关。PI3Kα/β或PI3Kα/δ抑制剂治疗可部分纠正骨髓增殖，不过PI3Kα/β抑制剂治疗的部分挽救效果更为显著。对药物处理的Dnmt3a–/– HSC/Ps进行的体内RNA测序分析表明，与对照组相比，趋化因子、炎症、细胞黏附和细胞外基质相关基因的表达有所降低。值得注意的是，经药物处理的白血病小鼠，在载体处理的Dnmt3a–/– LSK细胞中观察到的增强的胎肝HSC样基因特征出现逆转，且参与调节基于肌动蛋白细胞骨架功能的基因（包括RHO/RAC GTP酶）的表达也有所降低。在携带DNMT3A突变型AML的人源化异种移植（PDX）模型中，PI3Kα/β抑制剂治疗延长了小鼠生存期并减轻了白血病负担。我们的研究结果确定了一个治疗DNMT3A突变驱动的髓系恶性肿瘤的潜在新靶点。
Loss-of-function mutations in the DNA methyltransferase 3A (DNMT3A) are seen in a large number of patients with acute myeloid leukemia (AML) with normal cytogenetics and are frequently associated with poor prognosis. DNMT3A mutations are an early preleukemic event, which — when combined with other genetic lesions — result in full-blown leukemia. Here, we show that loss of Dnmt3a in hematopoietic stem and progenitor cells (HSC/Ps) results in myeloproliferation, which is associated with hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway. PI3Kα/β or the PI3Kα/δ inhibitor treatment partially corrects myeloproliferation, although the partial rescue is more efficient in response to the PI3Kα/β inhibitor treatment. In vivo RNA-Seq analysis on drug-treated Dnmt3a–/– HSC/Ps showed a reduction in the expression of genes associated with chemokines, inflammation, cell attachment, and extracellular matrix compared with controls. Remarkably, drug-treated leukemic mice showed a reversal in the enhanced fetal liver HSC-like gene signature observed in vehicle-treated Dnmt3a–/– LSK cells as well as a reduction in the expression of genes involved in regulating actin cytoskeleton-based functions, including the RHO/RAC GTPases. In a human PDX model bearing DNMT3A mutant AML, PI3Kα/β inhibitor treatment prolonged their survival and rescued the leukemic burden. Our results identify a potentially new target for treating DNMT3A mutation–driven myeloid malignancies.
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DOI：
10.1084/jem.20120993
发表时间：
2013-01-14
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Guiu J;Shimizu R;D'Altri T;Fraser ST;Hatakeyama J;Bresnick EH;Kageyama R;Dzierzak E;Yamamoto M;Espinosa L;Bigas A
通讯作者：
Bigas A
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
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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：
64.8
作者：
Dang, Irene;Gorelik, Roman;Gautreau, Alexis
通讯作者：
Gautreau, Alexis
影响因子：
20.3
作者：
Krishnan, Subha;Mali, Raghuveer Singh;Kapur, Reuben
通讯作者：
Kapur, Reuben
DOI：
10.1083/jcb.201407063
发表时间：
2014-12-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lorenzo DN;Badea A;Davis J;Hostettler J;He J;Zhong G;Zhuang X;Bennett V
通讯作者：
Bennett V