Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia

被引：96

作者：

Shojaee, Seyedmehdi ^{[1
]}

Caeser, Rebecca ^{[1
,14
]}

Buchner, Maike ^{[1
]}

Park, Eugene ^{[14
]}

Swaminathan, Srividya ^{[1
]}

Hurtz, Christian ^{[1
]}

Geng, Huimin ^{[1
]}

Chan, Lai N. ^{[1
]}

Klemm, Lars ^{[1
]}

Hofmann, Wolf-Karsten ^{[2
]}

Qiu, Yi Hua ^{[3
]}

Zhang, Nianxiang ^{[4
]}

Coombes, Kevin R. ^{[4
]}

Paietta, Elisabeth ^{[5
]}

Molkentin, Jeffery ^{[6
,7
]}

Koeffler, H. Phillip ^{[8
,9
]}

Willman, Cheryl L. ^{[10
]}

Hunger, Stephen P. ^{[11
]}

Melnick, Ari ^{[12
,13
]}

Kornblau, Steven M. ^{[3
]}

Mueschen, Markus ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA

[2] Heidelberg Univ, Med Fak Mannheim, Med Klin 3, D-68167 Heidelberg, Germany

[3] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[5] Albert Einstein Coll Med, Bronx, NY 10466 USA

[6] Univ Cincinnati, Howard Hughes Med Inst, Cincinnati, OH 45247 USA

[7] Univ Cincinnati, Cincinnati Childrens Hosp, Cincinnati, OH 45247 USA

[8] Cedars Sinai Med Ctr, Div Hematol & Oncol, Los Angeles, CA 90095 USA

[9] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117599, Singapore

[10] Univ New Mexico, Ctr Canc, Dept Pathol, Albuquerque, NM 87102 USA

[11] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[12] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[13] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA

[14] Univ Cambridge, Dept Haematol, Cambridge CB2 0AH, England

来源：

CANCER CELL | 2015年 / 28卷 / 01期

关键词：

KINASE; SPROUTY2; DUSP6; PROLIFERATION; INHIBITOR; MUTATIONS; PONATINIB; MOUSE; RAS; ABL;

D O I：

10.1016/j.ccell.2015.05.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2, Dusp6, and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance.

引用

页码：114 / 128

页数：15

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