Decoupling of tumor-initiating activity from stable immunophenotype in HoxA9-Meis1-driven AML.
Decoupling of tumor-initiating activity from stable immunophenotype in HoxA9-Meis1-driven AML.
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DOI：
10.1016/j.stem.2012.01.004
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发表时间：
2012-02-03
期刊：
影响因子：
23.9
通讯作者：
Nolan, Garry P.
中科院分区：
文献类型：
--
作者：
Gibbs, Kenneth D., Jr.;Jager, Astraea;Crespo, Oliver;Goltsev, Yury;Trejo, Angelica;Richard, Chase E.;Nolan, Garry P.
越来越多的证据表明肿瘤是由癌症干细胞维持的；然而，它们的性质仍然存在争议。在急性髓系白血病（AML）的HoxA9-Meis1 （H9M）模型中，我们发现肿瘤启动活性存在于三个免疫表型不同的室室中，对应于正常造血层次上的不同谱系-干细胞/祖细胞（Lin - kit+），以及髓系（Gr1+kit+）和淋巴系（Lym+kit+）的固定祖细胞。这些不同的肿瘤启动细胞（TIC）在体内克隆地再现了原始肿瘤的免疫表型谱（包括免疫表型分化程度较低的细胞）和共享的信号网络，因此，体内药物靶向保守的TIC生存途径（DNA甲基转移酶和MEK磷酸化）显著提高了生存率。总的来说，H9M AML被组织为一个非典型的等级，违反了严格的谱系标记界限和正常造血的单向分化。此外，这表明在某些恶性肿瘤中，肿瘤起始活性（或“癌干性”）可以代表独立于不同免疫表型定义存在的细胞状态。
Increasing evidence suggests tumors are maintained by cancer stem cells; however, their nature remains controversial. In a HoxA9-Meis1 (H9M) model of acute myeloid leukemia (AML), we found that tumor-initiating activity existed in three, immunophenotypically distinct compartments, corresponding to disparate lineages on the normal hematopoietic hierarchy—stem/progenitor cells (Lin−kit+), and committed progenitors of the myeloid (Gr1+kit+) and lymphoid lineages (Lym+kit+). These distinct tumor-initiating cells (TIC) clonally recapitulated the immunophenotypic spectrum of the original tumor in vivo (including cells with a less-differentiated immunophenotype) and shared signaling networks, such that in vivo pharmacologic targeting of conserved TIC survival pathways (DNA methyltransferase and MEK phosphorylation) significantly increased survival. Collectively, H9M AML is organized as an atypical hierarchy that defies the strict lineage marker boundaries and unidirectional differentiation of normal hematopoiesis. Moreover, this suggests that in certain malignancies tumor-initiation activity (or “cancer-stemness”) can represent a cellular state that exists independently of distinct immunophenotypic definition.
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CD47是人类急性髓样白血病干细胞的不良预后因素和治疗抗体靶标。
影响因子：
64.5
作者：
Majeti R;Chao MP;Alizadeh AA;Pang WW;Jaiswal S;Gibbs KD Jr;van Rooijen N;Weissman IL
通讯作者：
Weissman IL
影响因子：
20.3
作者：
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通讯作者：
Bonnet, Dominique
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.
DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP
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