title: 14-3-3 Integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1-transformed hematopoietic cells.
abstract: Human 8p11 stem cell leukemia/lymphoma syndrome usually presents as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase that plays a pathogenic role in hematopoietic transformation. We found that ZNF198-FGFR1 activated both the AKT and mitogen activated protein kinase (MAPK) prosurvival signaling pathways, resulting in elevated phosphorylation of the AKT target FOXO3a at T32 and BAD at S112, respectively. These phosphorylated residues subsequently sequestered the proapoptotic FOXO3a and BAD to 14-3-3 to prevent apoptosis. We used a peptide-based 14-3-3 competitive antagonist, R18, to disrupt 14-3-3-ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by ZNF198-FGFR1 compared with control cells. Moreover, purified recombinant transactivator of transcription (TAT)-conjugated R18 proteins effectively transduced into human leukemia cells and induced significant apoptosis in KG-1a cells expressing FGFR1OP2-FGFR1 fusion tyrosine kinase but not in control HL-60 and Jurkat T cells. Surprisingly, R18 was only able to dissociate FOXO3a, but not BAD as previously proposed, from 14-3-3 binding and induced apoptosis partially through liberation and reactivation of FOXO3a. Our findings suggest that 14-3-3 integrates prosurvival signals in FGFR1 fusion-transformed hematopoietic cells. Disrupting 14-3-3-ligand association may represent an effective therapeutic strategy to treat 8p11 stem cell MPD.
authors: Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Shaozhong
authors: S
authors: Dong
authors: Sumin
authors: S
authors: Kang
authors: Ting-Lei
authors: TL
authors: Gu
authors: Sean
authors: S
authors: Kardar
authors: Haian
authors: H
authors: Fu
authors: Sagar
authors: S
authors: Lonial
authors: Hanna Jean
authors: HJ
authors: Khoury
authors: Fadlo
authors: F
authors: Khuri
authors: Jing
authors: J
authors: Chen
mesh_terms: D048948:14-3-3 Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002882:Chromosomes, Human, Pair 13; D002898:Chromosomes, Human, Pair 8; D004268:DNA-Binding Proteins / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D048948:14-3-3 Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C111777:ZMYM2 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases