NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a

• Published in: Blood 2004-06, Vol.103 (12), p.4622-4629
• Main Authors: Gu, Ting-Lei, Tothova, Zuzana, Scheijen, Blanca, Griffin, James D., Gilliland, D. Gary, Sternberg, David W.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Division; Cell Line, Tumor; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Forkhead Box Protein O1; Forkhead Transcription Factors; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Large B-Cell, Diffuse - mortality; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphoma, T-Cell - mortality; Lymphoma, T-Cell - pathology; Medical sciences; Protein-Tyrosine Kinases - physiology; Signal Transduction; Survival Rate; Transcription Factors - genetics; Transcription Factors - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-03-0820

Between 30% and 50% of patients with advanced-stage anaplastic large-cell lymphoma (ALCL) harbor the balanced chromosomal rearrangement t(2;5)(p23;q35), which results in the generation of the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). To further study survival signaling by NPMALK, we generated Ba/F3 cell lines with either inducible or constitutive expression of NPM-ALK and examined the regulation of the AKT target FOXO3a. We hypothesized that NPM-ALK signaling through phosphoinositol 3-kinase (PI 3-kinase) and AKT would regulate FOXO3a, a member of the forkhead family of transcription factors, thereby stimulating proliferation and blocking programmed cell death in NPM-ALK-transformed cells. In Ba/F3 cells with induced or constitutive expression of NPM-ALK, concomitant AKT activation and phosphorylation of its substrate, FOXO3a, was observed. In addition, transient expression of NPM-ALK in U-20S cells inhibited FOXO3a-mediated transactivation of reporter gene expression. Furthermore, NPM-ALK-induced FOXO3a phosphorylation in Ba/F3 cells resulted in nuclear exclusion of this transcriptional regulator, up-regulation of cyclin D2 expression, and down-regulation of p27kip1 and Bim-1 expression. NPMALK reversal of proliferation arrest and of p27kip1 induction was dependent on the phosphorylation of FOXO3a. Thus, FOXO3a is a barrier to hematopoietic transformation that is overcome by phosphorylation and cytoplasmic relocalization induced by the expression of NPM-ALK. (Blood. 2004;103:4622-4629)