NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors

Chiarle, Roberto; Gong, Jerald Z.; Guasparri, Ilaria; Pesci, Anna; Cai, Jonjing; Liu, Jian; Simmons, William J.; Dhall, Girish; Howes, Jennifer E.; Piva, Roberto; Inghirami, Giorgio

doi:10.1182/blood-2002-05-1343

Cited by 231 publications

(217 citation statements)

References 36 publications

Supporting

Mentioning

210

Contrasting

Unclassified

Order By: Relevance

“…ALK fusion proteins have also been detected in a rare form of malignancy called inflammatory myofibroblastic tumor (10). Extensive analysis of the leukemogenic potential of NPM-ALK in animal models has further corroborated the importance of NPM-ALK and other ALK rearrangements in the development of ALK-positive ALCL and other diseases (11).…”

mentioning

confidence: 82%

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.

336

333

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 82%

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.

336

333

View full text Add to dashboard Cite

show abstract

“…The NPM/ ALK chimeric protein is constitutively expressed and activated through autophosphorylation (Shiota et al, 1994;Morris et al, 1997). NPM/ALK is highly oncogenic as documented both in vitro (Fujimoto et al, 1996;Bischof et al, 1997) and in vivo (Kuefer et al, 1997;Chiarle et al, 2003). NPM/ALK executes its oncogenicity by activating a number of signal transduction proteins, including signal transducer and activator of transcription 3 (STAT3) (Zhang et al, 2002;Chiarle et al, 2008;Li and Morris, 2008).…”

Section: Introductionmentioning

confidence: 99%

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

et al. 2010

View full text Add to dashboard Cite

“…The constitutive tyrosine kinase activity of NPM-ALK is responsible for malignant transformation of fibroblasts and lymphoid cells and was shown to induce Band T-cell lymphomas in transgenic mice (Chiarle et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

et al. 2007

View full text Add to dashboard Cite

The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60 c-src , Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.

show abstract

NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors

Cited by 231 publications

References 36 publications

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

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

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

Contact Info

Product

Resources

About