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.
复制标题
DOI：
10.1172/jci.insight.163864
复制
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.
登录
查看更多内容
DOI：
10.1084/jem.20120993
发表时间：
2013-01-14
期刊：
The Journal of experimental medicine
影响因子：
--
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：
--
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：
10.1056/nejmoa1005143
发表时间：
2010-12-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ley TJ;Ding L;Walter MJ;McLellan MD;Lamprecht T;Larson DE;Kandoth C;Payton JE;Baty J;Welch J;Harris CC;Lichti CF;Townsend RR;Fulton RS;Dooling DJ;Koboldt DC;Schmidt H;Zhang Q;Osborne JR;Lin L;O'Laughlin M;McMichael JF;Delehaunty KD;McGrath SD;Fulton LA;Magrini VJ;Vickery TL;Hundal J;Cook LL;Conyers JJ;Swift GW;Reed JP;Alldredge PA;Wylie T;Walker J;Kalicki J;Watson MA;Heath S;Shannon WD;Varghese N;Nagarajan R;Westervelt P;Tomasson MH;Link DC;Graubert TA;DiPersio JF;Mardis ER;Wilson RK
通讯作者：
Wilson RK