Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target

Roberto Chiarle; William J Simmons; Honjying Cai; Girish Dhall; Alberto Zamo; Regina Raz; James G Karras; David E Levy; Giorgio Inghirami

doi:10.1038/nm1249

Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target

Nat Med. 2005 Jun;11(6):623-9. doi: 10.1038/nm1249. Epub 2005 May 15.

Authors

Roberto Chiarle¹, William J Simmons, Honjying Cai, Girish Dhall, Alberto Zamo, Regina Raz, James G Karras, David E Levy, Giorgio Inghirami

Affiliation

¹ Department of Pathology and NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.

PMID: 15895073
DOI: 10.1038/nm1249

Abstract

Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Cell Line
Cell Transformation, Neoplastic*
DNA-Binding Proteins / physiology*
Fibroblasts / physiology
Humans
Lymphoma, Large B-Cell, Diffuse / physiopathology*
Lymphoma, T-Cell / physiopathology
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, Transgenic
Molecular Sequence Data
Multiple Myeloma / physiopathology
Oligonucleotides, Antisense / pharmacology
Protein-Tyrosine Kinases / physiology*
Proto-Oncogene Mas
Receptor Protein-Tyrosine Kinases
STAT3 Transcription Factor
Trans-Activators / physiology*

Substances

DNA-Binding Proteins
MAS1 protein, human
Oligonucleotides, Antisense
Proto-Oncogene Mas
STAT3 Transcription Factor
STAT3 protein, human
Stat3 protein, mouse
Trans-Activators
p80(NPM-ALK) protein
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Protein-Tyrosine Kinases
Receptor Protein-Tyrosine Kinases

Associated data

GENBANK/AF246978
GENBANK/AY572796
GENBANK/BC019168
GENBANK/U04946