Blood 2004;103:2787-2794
Coluccia AM, Perego S, Cleris L, Gunby RH, Passoni L, Marchesi E, Formelli
F, Gambacorti-Passerini C.
Deregulated apoptosis is a common finding in
tumorigenesis. The oncogenic tyrosine kinase nucleophosmin/anaplastic lymphoma
kinase (NPM/ALK) delivers a strong survival signal in anaplastic large cell
lymphomas (ALCLs). Although NPM/ ALK activates multiple antiapoptotic pathways,
the biologic relevance and therapeutic potential of more downstream apoptotic
effectors are mostly unknown.
In this report, the NPM/ALK-mediated induction of Bcl-XL (but not of Bcl-2) was
identified in human ALCL-derived cells. NPM/ALK kinase activity was required to
promote Bcl-XL expression and its protective effect on mitochondrial
homeostasis. Down-regulation of Bcl-XL significantly reduced the antiapoptotic
potential of NPM/ALK in both transformed murine Ba/F3 pro-B cells and human
ALCLderived KARPAS-299 cells. To elucidate the role of Bcl-XL in vivo, Ba/F3-NPM/ALK+
cells expressing a doxycycline (Dox)–inducible Bcl-XL antisense transgene (pTet-ON)
were injected into nude mice. Doxycycline administration prevented a fatal
systemic disease in 15 of 15 intravenously injected mice and the appearance of
subcutaneous tumor xenografts in 9 of 12 mice; in vivo downregulation of Bcl-XL
was also documented.
Our results show a pivotal role for Bcl-XL in ALK-mediated oncogenicity; a
single protein placed downstream of a known oncogene can be crucial for the
survival of neoplastic cells both in vitro and in vivo. Bcl-XL deserves further
investigation as a possible therapeutic target in ALK+ ALCLs.
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