Notch pathway activation targets AML-initiating cell homeostasis and differentiation

被引：136

作者：

Lobry, Camille ^{[1
,2
]}

Ntziachristos, Panagiotis ^{[1
,2
]}

Ndiaye-Lobry, Delphine ^{[1
,2
]}

Oh, Philmo ^{[1
,2
]}

Cimmino, Luisa ^{[1
,2
]}

Zhu, Nan ^{[4
,5
]}

Araldi, Elisa ^{[1
,2
]}

Hu, Wenhuo ^{[5
,7
,8
]}

Freund, Jacquelyn ^{[1
,2
]}

Abdel-Wahab, Omar ^{[5
,6
]}

Ibrahim, Sherif ^{[3
]}

Skokos, Dimitris ^{[9
]}

Armstrong, Scott A. ^{[4
,5
]}

Levine, Ross L. ^{[5
,6
]}

Park, Christopher Y. ^{[5
,7
,8
]}

Aifantis, Iannis ^{[1
,2
,3
]}

机构：

[1] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA

[2] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[3] NYU, Sch Med, Inst Canc, New York, NY 10016 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Leukemia Serv, Dept Med, New York, NY 10065 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Clin Labs, New York, NY 10065 USA

[9] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2013年 / 210卷 / 02期

基金：

美国国家卫生研究院;

关键词：

GENE-EXPRESSION SIGNATURE; HEMATOPOIETIC STEM-CELLS; ACUTE MYELOID-LEUKEMIA; TUMOR-SUPPRESSOR; LYMPHOBLASTIC-LEUKEMIA; MOLECULAR-GENETICS; TET2; INACTIVATION; PROGENITOR; MUTATIONS;

D O I：

10.1084/jem.20121484

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.

引用

页码：301 / 319

页数：19

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