NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors.
Anaplastic Large Cell Lymphomas (ALCLs) carry translocations in which the anaplastic lymphoma kinase (ALK) gene is juxtaposed to various genes, the most common of which is the NPM/B23 gene. ALK fusion proteins result in the constitutive activation of ALK tyrosine kinase, thereby enhancing proliferation and increasing cell survival. A direct role for NPM-ALK in cellular transformation has been shown in vitro with immortalized cell lines and in vivo using retroviral transfer experiments. Nonetheless, there is no direct evidence of its oncogenic potential in T lymphocytes, which represent the most common target of ALK chimeras. Here, we describe a new mouse model of lymphomagenesis in which human NPM-ALK transcription was targeted to T cells. NPM-ALK transgenic (Tg) mice were born with the expected mendelian distribution, normal lymphoid organs, and a normal number and proportion of helper and suppressor T cells. However, after a short period of latency, all NPM-ALK Tg mice developed malignant lymphoproliferative disorders (mean survival, 18 weeks). NPM-ALK Tg thymic lymphomas displayed a T-cell phenotype characteristic of immature thymocytes and frequently coexpressed surface CD30. A subset of the NPM-ALK Tg mice also developed clonal B-cell plasma cell neoplasms. These tumors arose in peripheral lymphoid organs (plasmacytomas) or within the bone marrow and often led to peripheral neuropathies and limb paralysis. Our NPM-ALK Tg mice are a suitable model to dissect the molecular mechanisms of ALK-mediated transformation and to investigate the efficacy of new therapeutic approaches for the treatment of human ALCL in vivo.
Chiarle
Roberto
R
Department of Pathology and Kaplan Comprehensive Cancer Center, and Department of Pediatric Oncology, New York University School of Medicine, New York, NY 10016, USA.
Gong
Jerald Z
JZ
Guasparri
Ilaria
I
Pesci
Anna
A
Cai
Jonjing
J
Liu
Jian
J
Simmons
William J
WJ
Dhall
Girish
G
Howes
Jennifer
J
Piva
Roberto
R
Inghirami
Giorgio
G
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D053616:Janus Kinase 3; D008221:Lymphoid Tissue / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D010954:Plasmacytoma / Q000235:genetics* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013953:Thymus Neoplasms / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3