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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-05-1343.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1919-1927
NEOPLASIA
NPM-ALK transgenic mice spontaneously develop T-cell
lymphomas and plasma cell tumors
Roberto Chiarle,
Jerald Z. Gong,
Ilaria Guasparri,
Anna Pesci,
Jonjing Cai,
Jian Liu,
William J. Simmons,
Girish Dhall,
Jennifer Howes,
Roberto Piva, and
Giorgio Inghirami
From the Department of Pathology and Kaplan
Comprehensive Cancer Center, and Department of Pediatric Oncology, New
York University School of Medicine, New York; Department of Pathology
and Centro di Ricerca in Medicina Sperimentale (CERMS), University of
Torino, Torino, Italy; Department of Pathology, University
of Verona, Verona, Italy; Department of Pathology,
University of Cornell, New York, NY.
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.
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