Inhibition of Anaplastic Lymphoma Kinase (ALK) Activity Provides a Therapeutic Approach for CLTC-ALK-Positive Human Diffuse Large B Cell Lymphomas

被引：44

作者：

Cerchietti, Leandro ^{[1
,2
]}

Damm-Welk, Christine ^{[3
]}

Vater, Inga ^{[4
]}

Klapper, Wolfram ^{[5
,6
]}

Harder, Lana ^{[4
]}

Pott, Christiane ^{[7
]}

Yang, Shao Ning ^{[1
,2
]}

Reiter, Alfred ^{[3
]}

Siebert, Reiner ^{[5
,6
]}

Melnick, Ari ^{[1
,2
]}

Woessmann, Willi ^{[3
]}

机构：

[1] Cornell Univ, Weill Cornell Med Coll, Div Hematol & Oncol, New York, NY 10021 USA

[2] Cornell Univ, Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA

[3] Univ Giessen, Dept Pediat Hematol & Oncol, Giessen, Germany

[4] Univ Kiel, Inst Human Genet, Kiel, Germany

[5] Univ Hosp Schleswig Holstein, Dept Pathol, Hematopathol Sect, Kiel, Germany

[6] Univ Hosp Schleswig Holstein, Lymph Node Registry, Kiel, Germany

[7] Univ Kiel, Dept Med 2, Kiel, Germany

来源：

PLOS ONE | 2011年 / 6卷 / 04期

关键词：

NPM-ALK; FUSION; STAT3; TRANSFORMATION; PROTEINS; CHILDREN; CANCER;

D O I：

10.1371/journal.pone.0018436

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.

引用

页数：11

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