Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target.

Abstract

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 nonneural cells results from chromosomal translocations that create novel fusion proteins. These protein hybrids compose the proximal part of a partner gene, including its promoter region, and the distal part of ALK, including the coding sequence for the entire kinase domain. ALK was first identified in a subset of T-cell lymphomas with anaplastic large cell lymphoma (ALCL) 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 being the STAT3 pathway, normally activated by cytokines from the interleukin-2 (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 antitumor immune response, protection from hypoxia, angiogenesis, DNA repair, cell migration and invasiveness, and cell metabolism. In addition, NPM-ALK uses epigenetic silencing mechanisms to downregulate 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.

• Authors: Michael T Werner, Chen Zhao, Qian Zhang, Mariusz A Wasik
• Journal: Blood (Blood) Vol. 129 Issue 7 Pg. 823-831 (02 16 2017) ISSN: 1528-0020 [Electronic] United States
• PMID: 27879258 (Publication Type: Journal Article, Review)
• Copyright: © 2017 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents
• Cytokines
• MicroRNAs
• NPM1 protein, human
• Nuclear Proteins
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• Nucleophosmin
• p80(NPM-ALK) protein
• ALK protein, human
• Anaplastic Lymphoma Kinase
• Protein-Tyrosine Kinases
• Receptor Protein-Tyrosine Kinases

Topics

• Anaplastic Lymphoma Kinase
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• CD4-Positive T-Lymphocytes (metabolism, pathology)
• Cell Transformation, Neoplastic (drug effects, genetics, metabolism, pathology)
• Cytokines (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lymphoma, Large-Cell, Anaplastic (drug therapy, genetics, metabolism, pathology)
• Lymphoma, T-Cell (drug therapy, genetics, metabolism, pathology)
• MicroRNAs (genetics, metabolism)
• Molecular Targeted Therapy (methods)
• Nuclear Proteins (antagonists & inhibitors, genetics, metabolism)
• Nucleophosmin
• Oncogene Proteins, Fusion (antagonists & inhibitors, genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)