Increase sensitivity to chemotherapeutical agents and cytoplasmatic interaction between NPM leukemic mutant and NF-kappaB in AML carrying NPM1 mutations.
Mutations in nucleophosmin (NPM) exon 12 and the resulting delocalization of NPM into the cytoplasm are the most specific and frequent cellular events in acute myeloid leukemia patients (AML) with normal karyotype. Cytoplasmatic NPM (NPMc+) is associated with responsiveness to chemotherapy and better prognosis. The activation of nuclear factor-kappaB (NF-kappaB) has been demonstrated to occur in a subset of AML patients and is thought to induce resistance to many chemotherapeutical agents. In this study, we demonstrate the increased in vitro sensitivity of NPMc+ cells to chemotherapeutical agents and their reduced NF-kappaB activity. Furthermore, we provide evidence of the interaction between NPMc+ and NF-kappaB in the cytoplasm, resulting in the sequestration and inactivation of NF-kappaB. The cytosolic localization and consequent inactivation of NF-kappaB justifies the reduced NF-kappaB DNA-binding activity observed in NPMc+ patients. These data, taken together, may provide a possible explanation for the increased rate of chemosensitivity observed among the NPMc+ patients.
Cilloni
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Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences of the University of Turin, Turin, Italy. daniela.cilloni@unito.it
Messa
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Rosso
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Arruga
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Defilippi
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Carturan
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Catalano
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Pautasso
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Panuzzo
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Nicoli
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Messa
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Morotti
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Iacobucci
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Martinelli
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Bracco
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D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D003630:Daunorubicin / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D047468:Immunoprecipitation; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D003561:Cytarabine; D000090243:Nucleophosmin; D005047:Etoposide; D003630:Daunorubicin