Sporadic variant 2p23/ALK abnormalities identified in ALK-positive ALCL indicate that genes other than NPM may also be involved in the deregulation of ALK and lymphomagenesis.
The NPM-ALK chimeric protein is an activated tyrosine kinase that has been shown to be a potent oncogene and presumably plays a causative role in lymphomagenesis.
These translocations induce the ectopic expression of X-ALK proteins, thought to be involved in lymphomagenesis, through the dysregulation of cell proliferation and apoptotic pathways.
Recently, the essential role of STAT3 activation as well as STAT 5 activation in nucleophosmin-ALK fusion protein-mediated lymphomagenesis was reported.
To elucidate the ALK pathways sustaining lymphomagenesis and tumor maintenance, we analyzed the tyrosine-kinase protein profiles of ALK-positive cell lines using 2 complementary proteomic-based approaches, taking advantage of a specific ALK RNA interference (RNAi) or cell-permeable inhibitors.
Although the t(2;5) product nucleophosmin-ALK has been extensively studied for its transforming properties, very little is known regarding cooperative genetic mutations that may contribute to lymphomagenesis and may predict survival outcome, specifically in a purely pediatric population.
To unravel the regulatory network underlying nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) -mediated lymphomagenesis of anaplastic large-cell lymphoma (ALCL) and to discover diagnostic genomic classifiers for the recognition of patients with ALK-positive and ALK-negative ALCL among T-cell non-Hodgkin's lymphoma (T-NHL).
We report here the development of novel conditional mouse models for ALK-induced lymphomagenesis, with the use of the tetracycline regulatory system under the control of the EmuSRalpha enhancer/promoter.
Analysis of NPM-ALKlymphomagenesis in transgenic mice showed p16INK4a-dependent accumulation of senescent cells in premalignant lesions and decreased tumor latency in the absence of p16INK4a.
The dichloromethane extract of the ethnomedicinal plant Neurolaena lobata inhibits NPM/ALK expression which is causal for anaplastic large cell lymphomagenesis.
The gene fusion product and the transcription factor STAT3 are both phosphorylated, and thereby the pathogenetic mechanism of this case shows important analogies with that of NPM-ALK and CLTC-ALK lymphomas, in which STAT3 plays a central role in the lymphomagenesis.
In this review, we will first outline how these different cell and mouse models were designed, and what key findings they revealed (or confirmed) towards oncogenic ALK-induced lymphomagenesis.