Abstract
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product with tyrosine kinase activity and is expressed in substantial subset of anaplastic large cell lymphomas (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3). Although NPM-ALK+ ALCL overall shows a better prognosis, there is a sub-group of patients who relapses and is resistant to conventional chemotherapeutic regimens. NPM-ALK is a potential target for small molecule kinase inhibitors. Crizotinib (PF-2341066) is a small, orally bioavailable molecule that inhibits growth of tumors with ALK activity as shown in a subgroup of non-small lung cancer patients with EML4-ALK expression. In this study, we have investigated the in vitro effects of Crizotinib in ALCL cell line with NPM-ALK fusion. Crizotinib induced marked downregulation of STAT3 phosphorylation, which was associated with significant apoptotic cell death. Apoptosis induction was attributed to caspase-3 cleavage and marked downregulation of the Bcl-2 family of proteins including MCL-1. These findings implicate that Crizotinib has excellent potential to treat patients with NPM-ALK+ ALCL through induction of apoptotic cell death and downregulation of major oncogenic proteins in this aggressive lymphoma.
Original language | English (US) |
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Pages (from-to) | 503-508 |
Number of pages | 6 |
Journal | Leukemia Research |
Volume | 38 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2014 |
Keywords
- ALCL
- Crizotinib
- MCL-1
- NPM-ALK
- STAT3
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research