What have we learnt from mouse models of NPM-ALK-induced lymphomagenesis?

Turner, Suzanne D.; Alexander, Denis R.

doi:10.1038/sj.leu.2403797

Cited by 40 publications

(28 citation statements)

References 58 publications

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“…In 2003, a mouse model was generated in which the expression of NPM-ALK, under the control of the CD4 promoter (Chiarle et al 2003), showed the spontaneous development of T-cell lymphomas and/or plasmacytomas, confirming the lymphomagenic role of NPM-ALK, providing a valuable tool for the study of ALCL. These findings were then confirmed using additional mouse models (Turner & Alexander 2005).…”

Section: Alk Expression In Hematological Disorderssupporting

confidence: 65%

Anaplastic lymphoma kinase in human cancer

Barreca

Lasorsa

Riera

et al. 2011

Journal of Molecular Endocrinology

120

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The receptor tyrosine kinases (RTKs) play a critical role, controlling cell proliferation, survival, and differentiation of normal cells. Their pivotal function has been firmly established in the pathogenesis of many cancers as well. The anaplastic lymphoma kinase (ALK), a transmembrane RTK, originally identified in the nucleophosmin (NPM)-ALK chimera of anaplastic large cell lymphoma, has emerged as a novel tumorigenic player in several human cancers. In this review, we describe the expression of the ALK-RTK, its related fusion proteins, and their molecular mechanisms of activation. Novel tailored strategies are briefly illustrated for the treatment of ALK-positive neoplasms.

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Section: Alk Expression In Hematological Disorderssupporting

confidence: 65%

Anaplastic lymphoma kinase in human cancer

Barreca

Lasorsa

Riera

et al. 2011

Journal of Molecular Endocrinology

120

View full text Add to dashboard Cite

show abstract

“…Approximately 50-60% of cases of ALCL are associated with the t(2;5;)(p23;q35) chromosomal translocation, which generates a hybrid gene consisting of the intracellular domain of the ALK tyrosine kinase receptor juxtaposed with NPM. The resulting fusion protein, NPM-ALK has constitutive tyrosine kinase activity and has been shown to transform various hematopoietic cell types in vitro and support tumor formation in vivo (1,6). Other less frequent ALK fusion partners, e.g., tropomyosin-3 and clathrin heavy chain, have also been identified in ALCL as well as in CD30-negative diffuse large-cell lymphoma (1,2,7,8).…”

mentioning

confidence: 99%

Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK

Galkin

Melnick

Kim

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

334

333

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Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC 50 values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo , NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.

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“…32 A direct role for NPM-ALK in cellular transformation has been shown both in vitro and in vivo, and such studies have shed light on the mechanisms of malignant transformation by this oncoprotein. 33,34 These mechanisms include activation of several downstream signal-transduction pathways, which regulate cell survival, proliferation, migration and, more recently, hypoxia. 20,24 Although hypoxia has been reported to upregulate HIF-1a and VEGF in ALK-positive (ALK þ ) ALCL, 20 so far no studies have implicated it in angiogenesis in ALK tumor development.…”

Section: Discussionmentioning

confidence: 99%