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Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK): the ultimate oncogene and therapeutic target.

著者 Werner MT , Zhao C , Zhang Q , Wasik MA
Blood.2016 Nov 22 ; ():.
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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase physiologically expressed by fetal neural cells. However, aberrantly expressed ALK is involved in the pathogenesis of diverse malignancies including distinct types of lymphoma, lung carcinoma, and neuroblastoma. The aberrant ALK expression in non-neural cells results from chromosomal translocations that create novel fusion proteins. These protein hybrids are comprised of the proximal part of a partner gene including its promoter region and the distal part of ALK including coding sequence for the entire kinase domain. ALK was first identified in a subset of T-cell lymphomas with anaplastic large cell morphology (ALK+ALCL), the vast majority of which harbor the well-characterized nucleophosmin (NPM)-ALK fusion protein. NPM-ALK co-opts several intracellular signal transduction pathways, foremost the STAT3 pathway, normally activated by cytokines from the IL-2 family to promote cell proliferation and to inhibit apoptosis. Many genes and proteins modulated by NPM-ALK are also involved in evasion of anti-tumor immune response, protection from hypoxia, angiogenesis, DNA repair, cell migration and invasiveness, as well as cell metabolism. In addition, NPM-ALK uses epigenetic silencing mechanisms to down-regulate tumor suppressor genes to maintain its own expression. Importantly, NPM-ALK is capable of transforming primary human CD4+ T-cells into immortalized cell lines indistinguishable from patient-derived ALK+ALCL. Preliminary clinical studies indicate that inhibition of NPM-ALK induces long-lasting complete remissions in a large subset of heavily pretreated adult patients and the vast majority of children with high-stage ALK+ALCL. Combining ALK inhibition with other novel therapeutic modalities should prove even more effective.
PMID: 27879258 [PubMed - as supplied by publisher]
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