DNMT3A mutation leads to leukemic extramedullary infiltration mediated by TWIST1.
DNMT3A mutation leads to leukemic extramedullary infiltration mediated by TWIST1.
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DNMT3A突变导致TWIST1介导的白血病髓外浸润
DOI：
10.1186/s13045-016-0337-3
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发表时间：
2016-10-10
影响因子：
28.5
通讯作者：
Chen SJ
中科院分区：
文献类型：
--
作者：
Xu J;Zhang W;Yan XJ;Lin XQ;Li W;Mi JQ;Li JM;Zhu J;Chen Z;Chen SJ
DNMT 3A突变经常在急性髓系白血病（AML）中发现，并与不良结局相关。最近，AML髓外疾病的复发病例报告显示，在脑脊液中检测到携带DNMT 3A变异的AML细胞。然而，DNMT 3A突变（D3 Amut）和髓外浸润（EMI）之间是否存在因果关系尚不清楚。我们利用携带DNMT 3A（R882 C）突变的AML细胞株，即OCI-AML 3，评估其体外和体内迁移能力。利用RNA干扰技术和异种移植小鼠模型，研究DNMT 3A基因突变对细胞运动性的影响，并探讨其可能的机制。OCI-AML 3在体外表现出极强的迁移能力，经静脉输注后可浸润NOD/SCID小鼠脑膜。我们发现，这种白血病的迁移或浸润能力显着受损的DNMT 3A突变体的敲低。值得注意的是，TWIST 1，上皮-间质转化的关键诱导剂，其是癌转移的基础，与R882突变相关地高度表达。DNMT 3A突变细胞中TWIST 1的去除大大削弱了它们的移动性或浸润性。我们的研究结果表明OCI-AML 3株中的D3 Amut通过促进EMI过程增强白血病侵袭性，这部分是通过上调TWIST 1。本文的在线版本（doi：10.1186/s13045-016-0337-3）包含补充材料，可供授权用户使用。
DNMT3A mutations are frequently discovered in acute myeloid leukemia (AML), associated with poor outcome. Recently, a relapse case report of AML extramedullary disease has showed that AML cells harboring DNMT3A variation were detected in the cerebral spinal fluid. However, whether a causal relationship exists between DNMT3A mutation (D3Amut) and extramedullary infiltration (EMI) is unclear. We took advantage of DNMT3A (R882C) mutation-carrying AML cell strain, that is, OCI-AML3, assessing its migration ability in vitro and in vivo. By RNA interfering technology and a xenograft mouse model, we evaluated the effect of DNMT3A mutation on cell mobility and explored the possible mechanism. OCI-AML3 displayed extraordinary migration ability in vitro and infiltrated into meninges of NOD/SCID mice after intravenous transfusion. We found that this leukemic migration or infiltration capacity was significantly compromised by the knockdown of DNMT3A mutant. Notably, TWIST1, a critical inducer of epithelial–mesenchymal transition, which underlies the metastasis of carcinomas, was highly expressed in association with R882 mutations. Abrogation of TWIST1 in DNMT3A mutated cells considerably weakened their mobility or infiltration. Our results demonstrate that D3Amut in OCI-AML3 strain enhances leukemic aggressiveness by promoting EMI process, which is partially through upregulating TWIST1. The online version of this article (doi:10.1186/s13045-016-0337-3) contains supplementary material, which is available to authorized users.
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DOI：
10.1158/1078-0432.ccr-14-0327
发表时间：
2015-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Sehgal AR;Gimotty PA;Zhao J;Hsu JM;Daber R;Morrissette JD;Luger S;Loren AW;Carroll M
通讯作者：
Carroll M
DOI：
10.6004/jnccn.2012.0120
发表时间：
2012-09-01
影响因子：
13.4
作者：
Slomowitz, Samuel J.;Shami, Paul J.
通讯作者：
Shami, Paul J.
影响因子：
2.7
作者：
Shimizu, Hiroaki;Saitoh, Takayuki;Nojima, Yoshihisa
通讯作者：
Nojima, Yoshihisa
影响因子：
6.2
作者：
Shihadeh, Ferial;Reed, Valerie;Dabaja, Bouthaina
通讯作者：
Dabaja, Bouthaina
DOI：
10.1056/nejmoa1301689
发表时间：
2013-05-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cancer Genome Atlas Research Network;Ley TJ;Miller C;Ding L;Raphael BJ;Mungall AJ;Robertson A;Hoadley K;Triche TJ Jr;Laird PW;Baty JD;Fulton LL;Fulton R;Heath SE;Kalicki-Veizer J;Kandoth C;Klco JM;Koboldt DC;Kanchi KL;Kulkarni S;Lamprecht TL;Larson DE;Lin L;Lu C;McLellan MD;McMichael JF;Payton J;Schmidt H;Spencer DH;Tomasson MH;Wallis JW;Wartman LD;Watson MA;Welch J;Wendl MC;Ally A;Balasundaram M;Birol I;Butterfield Y;Chiu R;Chu A;Chuah E;Chun HJ;Corbett R;Dhalla N;Guin R;He A;Hirst C;Hirst M;Holt RA;Jones S;Karsan A;Lee D;Li HI;Marra MA;Mayo M;Moore RA;Mungall K;Parker J;Pleasance E;Plettner P;Schein J;Stoll D;Swanson L;Tam A;Thiessen N;Varhol R;Wye N;Zhao Y;Gabriel S;Getz G;Sougnez C;Zou L;Leiserson MD;Vandin F;Wu HT;Applebaum F;Baylin SB;Akbani R;Broom BM;Chen K;Motter TC;Nguyen K;Weinstein JN;Zhang N;Ferguson ML;Adams C;Black A;Bowen J;Gastier-Foster J;Grossman T;Lichtenberg T;Wise L;Davidsen T;Demchok JA;Shaw KR;Sheth M;Sofia HJ;Yang L;Downing JR;Eley G
通讯作者：
Eley G