Abstract
AbstractAnaplastic large-cell lymphomas (ALCLs) carry chromosome translocations in which the anaplastic lymphoma kinase (ALK) gene is fused to several partners, most frequently, the NPM1 gene. We have demonstrated that the constitutive activation of ALK fusion proteins results in cellular transformation and lymphoid neoplasia. Herein, we specifically down-regulated ALK protein expression by using small hairpin RNA (shRNA) targeting a sequence coding for the catalytic domain of ALK. The ablation of ALK leads to the down-modulation of known ALK downstream effectors, cell growth arrest, and reversion of the transformed phenotype of ALK+ mouse embryonic fibroblasts in vitro and in vivo. In human ALCL cells lentiviral-mediated ALK knock-down leads to G1 cell-cycle arrest and apoptosis in vitro and tumor growth inhibition and regression in vivo. Using a specific approach we have demonstrated that the survival and growth of ALK+ ALCLs are strictly dependent on ALK activation and signaling. Therefore, ALK is a viable target for therapeutic intervention and its inactivation might represent a pivotal approach for the treatment of ALK lymphomas and other ALK-dependent human tumors.
Highlights
Introduction a sequence coding for the catalytic domain of anaplastic lymphoma kinase (ALK)
We designed small hairpin RNA (shRNA) spanning the cytoplasmic domain of ALK receptor (ALK-R) since this region is conserved in all oncogenic fusion proteins.[3]
We reasoned that a functional shRNA recognizing the cytoplasmic moiety would result in broad-spectrum inhibition of ALK expression, targeting all ALK chimeras and ALK-R
Summary
Introduction a sequence coding for the catalytic domain of ALK. The ablation of ALK leads to the down-modulation of known ALK downstream effectors, cell growth arrest, and reversion of the transformed phenotype of ALK؉ mouse embryonic fibroblasts in vitro and in vivo. PLC-␥, PI3K, and Jak[3] lead to the activation of numerous downstream molecules including cyclin D, Erk1/2, STAT3, and AKT.[19,20] Using cell lineage–specific conditional knock-out models, we have recently demonstrated that the genetic ablation of STAT3 in ALKϩ cells leads to T- and B-cell death, and prevents the generation of B-cell neoplasms.[21] Previously, PLC-␥ and AKT have been shown to play an essential role in ALK-mediated transformation, in vitro.[16,22,23,24] it is conceivable that the inhibition of ALK could induce biologic changes capable of inhibiting cell growth and/or promoting cell death This hypothesis is supported by a study in which a nonselective, but active drug against ALK was shown to successfully lead to tumor cell death.[25] the specific down-modulation of NPMALK mRNA via siRNA does not induce apoptosis, despite a significant reduction in NPM-ALK protein.[26] the formal demonstration that the specific loss of ALK kinase activity has relevant biologic effects is still missing. Solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734
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