Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML.
Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML.
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DOI：
10.1038/s41375-018-0180-3
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发表时间：
2019-01
期刊：
影响因子：
11.4
通讯作者：
Subklewe M
中科院分区：
文献类型：
--
作者：
Haubner S;Perna F;Köhnke T;Schmidt C;Berman S;Augsberger C;Schnorfeil FM;Krupka C;Lichtenegger FS;Liu X;Kerbs P;Schneider S;Metzeler KH;Spiekermann K;Hiddemann W;Greif PA;Herold T;Sadelain M;Subklewe M
急性髓性白血病（AML）的靶向免疫治疗受到缺乏AML特异性靶抗原和克隆异质性的挑战，导致不必要的靶向非白血病毒性和小克隆复发的风险。我们假设联合靶向AML细胞可以在不增加毒性的情况下提高治疗效果。为了确定AML和白血病干细胞特异性的靶抗原组合，我们基于原发性AML （n = 356）和正常骨髓样本（n = 34）的流式细胞术，以及最近报道的正常组织蛋白质组学数据集，生成了详细的蛋白质表达谱。我们分析了初始诊断（n = 302）和复发（n = 54）时AML大块和白血病干细胞中CD33、CD123、CLL1、TIM3、CD244和CD7的抗原表达水平。CD33, CD123, CLL1， TIM3和CD244在初始诊断和复发时在AML体细胞上普遍表达，与遗传特征无关。对于每一个分析的目标，我们在不同的正常造血人群中发现了额外的表达。分析我们的六个靶点在所有双重组合中的共表达（n = 15），我们发现CD33/TIM3和CLL1/TIM3在AML中与正常造血组织和非造血组织相比高度阳性。我们的研究结果表明，联合靶向CD33/TIM3或CLL1/TIM3可以提高AML免疫治疗的疗效，而不会加重毒性。
Targeted immunotherapy in acute myeloid leukemia (AML) is challenged by the lack of AML-specific target antigens and clonal heterogeneity, leading to unwanted on-target off-leukemia toxicity and risk of relapse from minor clones. We hypothesize that combinatorial targeting of AML cells can enhance therapeutic efficacy without increasing toxicity. To identify target antigen combinations specific for AML and leukemic stem cells, we generated a detailed protein expression profile based on flow cytometry of primary AML (n = 356) and normal bone marrow samples (n = 34), and a recently reported integrated normal tissue proteomic data set. We analyzed antigen expression levels of CD33, CD123, CLL1, TIM3, CD244 and CD7 on AML bulk and leukemic stem cells at initial diagnosis (n = 302) and relapse (n = 54). CD33, CD123, CLL1, TIM3 and CD244 were ubiquitously expressed on AML bulk cells at initial diagnosis and relapse, irrespective of genetic characteristics. For each analyzed target, we found additional expression in different populations of normal hematopoiesis. Analyzing the coexpression of our six targets in all dual combinations (n = 15), we found CD33/TIM3 and CLL1/TIM3 to be highly positive in AML compared with normal hematopoiesis and non-hematopoietic tissues. Our findings indicate that combinatorial targeting of CD33/TIM3 or CLL1/TIM3 may enhance therapeutic efficacy without aggravating toxicity in immunotherapy of AML.
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DOI：
10.1056/nejmoa1609783
发表时间：
2017-03-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kantarjian H;Stein A;Gökbuget N;Fielding AK;Schuh AC;Ribera JM;Wei A;Dombret H;Foà R;Bassan R;Arslan Ö;Sanz MA;Bergeron J;Demirkan F;Lech-Maranda E;Rambaldi A;Thomas X;Horst HA;Brüggemann M;Klapper W;Wood BL;Fleishman A;Nagorsen D;Holland C;Zimmerman Z;Topp MS
通讯作者：
Topp MS
影响因子：
45.3
作者：
Breems, DA;Van Putten, WLJ;Löwenberg, B
通讯作者：
Löwenberg, B
影响因子：
11.4
作者：
Kenderian SS;Ruella M;Shestova O;Klichinsky M;Aikawa V;Morrissette JJ;Scholler J;Song D;Porter DL;Carroll M;June CH;Gill S
通讯作者：
Gill S
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M
影响因子：
12.8
作者：
Ehninger, A.;Kramer, M.;Roellig, C.;Thiede, C.;Bornhaeuser, M.;von Bonin, M.;Wermke, M.;Feldmann, A.;Bachmann, M.;Ehninger, G.;Oelschlaegel, U.
通讯作者：
Oelschlaegel, U.