Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib.
Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib.
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DOI：
10.1038/s41591-018-0115-6
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发表时间：
2018-08
期刊：
影响因子：
82.9
通讯作者：
Vyas P
中科院分区：
文献类型：
--
作者：
Quek L;David MD;Kennedy A;Metzner M;Amatangelo M;Shih A;Stoilova B;Quivoron C;Heiblig M;Willekens C;Saada V;Alsafadi S;Vijayabaskar MS;Peniket A;Bernard OA;Agresta S;Yen K;MacBeth K;Stein E;Vassiliou GS;Levine R;De Botton S;Thakurta A;Penard-Lacronique V;Vyas P
编码异柠檬酸脱氢酶2（IDH 2）的基因突变发生在几种类型的癌症中，包括急性髓性白血病（AML）。在模型系统中，突变IDH 2导致造血分化停滞。Enasidenib是突变IDH 2的选择性小分子抑制剂，通过促进白血病细胞分化，在40%的复发/难治性AML患者中产生临床反应。在这里，我们研究了对enasidenib治疗的反应和获得性抗性的克隆基础。使用连续的患者样本，我们确定了造血细胞群体在不同分化阶段的克隆结构。治疗前IDH 2突变体克隆显示可变的分化停滞。Enasidenib处理促进了造血细胞从终末或祖先突变克隆的分化;处理促进非突变细胞的分化的频率较低。配对诊断/复发样品的分析未鉴定复发时IDH 2中的第二位点突变。相反，复发是由终末或祖先克隆的克隆进化或选择引起的，突出了可能被靶向以恢复分化停滞的多个旁路途径。在治疗过程中不同分化阶段的细胞群中绘制克隆结构图，说明了不同克隆在复发期间如何响应和进化。
Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated relapsed/ refractory AML patients by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Pre-therapy IDH2 mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of non-mutant cells. Analysis of paired diagnosis/relapse samples did not identify second site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution, or selection, of terminal or ancestral clones, highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. Mapping clonal structure in cell populations at different stages of differentiation during therapy illustrates how different clones respond and evolve during relapse.
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影响因子：
30.8
作者：
Faber ZJ;Chen X;Gedman AL;Boggs K;Cheng J;Ma J;Radtke I;Chao JR;Walsh MP;Song G;Andersson AK;Dang J;Dong L;Liu Y;Huether R;Cai Z;Mulder H;Wu G;Edmonson M;Rusch M;Qu C;Li Y;Vadodaria B;Wang J;Hedlund E;Cao X;Yergeau D;Nakitandwe J;Pounds SB;Shurtleff S;Fulton RS;Fulton LL;Easton J;Parganas E;Pui CH;Rubnitz JE;Ding L;Mardis ER;Wilson RK;Gruber TA;Mullighan CG;Schlenk RF;Paschka P;Döhner K;Döhner H;Bullinger L;Zhang J;Klco JM;Downing JR
通讯作者：
Downing JR
影响因子：
48
作者：
Katz, Yarden;Wang, Eric T.;Airoldi, Edoardo M.;Burge, Christopher B.
通讯作者：
Burge, Christopher B.
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B
影响因子：
64.8
作者：
Abbosh C;Birkbak NJ;Wilson GA;Jamal-Hanjani M;Constantin T;Salari R;Le Quesne J;Moore DA;Veeriah S;Rosenthal R;Marafioti T;Kirkizlar E;Watkins TBK;McGranahan N;Ward S;Martinson L;Riley J;Fraioli F;Al Bakir M;Grönroos E;Zambrana F;Endozo R;Bi WL;Fennessy FM;Sponer N;Johnson D;Laycock J;Shafi S;Czyzewska-Khan J;Rowan A;Chambers T;Matthews N;Turajlic S;Hiley C;Lee SM;Forster MD;Ahmad T;Falzon M;Borg E;Lawrence D;Hayward M;Kolvekar S;Panagiotopoulos N;Janes SM;Thakrar R;Ahmed A;Blackhall F;Summers Y;Hafez D;Naik A;Ganguly A;Kareht S;Shah R;Joseph L;Marie Quinn A;Crosbie PA;Naidu B;Middleton G;Langman G;Trotter S;Nicolson M;Remmen H;Kerr K;Chetty M;Gomersall L;Fennell DA;Nakas A;Rathinam S;Anand G;Khan S;Russell P;Ezhil V;Ismail B;Irvin-Sellers M;Prakash V;Lester JF;Kornaszewska M;Attanoos R;Adams H;Davies H;Oukrif D;Akarca AU;Hartley JA;Lowe HL;Lock S;Iles N;Bell H;Ngai Y;Elgar G;Szallasi Z;Schwarz RF;Herrero J;Stewart A;Quezada SA;Peggs KS;Van Loo P;Dive C;Lin CJ;Rabinowitz M;Aerts HJWL;Hackshaw A;Shaw JA;Zimmermann BG;TRACERx consortium;PEACE consortium;Swanton C
通讯作者：
Swanton C