title: The transcription factors Ik-1 and MZF1 downregulate IGF-IR expression in NPM-ALK⁺ T-cell lymphoma.
abstract: BACKGROUND
  The type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase promotes the survival of an aggressive subtype of T-cell lymphoma by interacting with nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogenic protein. NPM-ALK(+) T-cell lymphoma exhibits much higher levels of IGF-IR than normal human T lymphocytes. The mechanisms underlying increased expression of IGF-IR in this lymphoma are not known. We hypothesized that upregulation of IGF-IR could be attributed to previously unrecognized defects that inherently exist in the transcriptional machinery in NPM-ALK(+) T-cell lymphoma.
  
  
  RESULTS
  Screening studies showed substantially lower levels of the transcription factors Ikaros isoform 1 (Ik-1) and myeloid zinc finger 1 (MZF1) in NPM-ALK(+) T-cell lymphoma cell lines and primary tumor tissues from patients than in human T lymphocytes. A luciferase assay supported that Ik-1 and MZF1 suppress IGF-IR gene promoter. Furthermore, ChIP assay showed that these transcription factors bind specific sites located within the IGF-IR gene promoter. Forced expression of Ik-1 or MZF1 in the lymphoma cells decreased IGF-IR mRNA and protein. This decrease was associated with downregulation of pIGF-IR, and the phosphorylation of its interacting proteins IRS-1, AKT, and NPM-ALK. In addition, overexpression of Ik-1 and MZF1 decreased the viability, proliferation, migration, and anchorage-independent colony formation of the lymphoma cells.
  
  
  CONCLUSIONS
  Our results provide novel evidence that the aberrant decreases in Ik-1 and MZF1 contribute significantly to the pathogenesis of NPM-ALK(+) T-cell lymphoma through the upregulation of IGF-IR expression. These findings could be exploited to devise new strategies to eradicate this lymphoma.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA. dtvishwa@mdanderson.org.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. dtvishwa@mdanderson.org.
authors.forename: Deeksha
authors.initials: D
authors.lastname: Vishwamitra
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA. cvcurry@texaschildrens.org.
authors.forename: Choladda V
authors.initials: CV
authors.lastname: Curry
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA. Serhan.Alkan@cshs.org.
authors.forename: Serhan
authors.initials: S
authors.lastname: Alkan
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China. yaohua_song1@yahoo.com.
authors.forename: Yao-Hua
authors.initials: YH
authors.lastname: Song
authors.affiliation: The University of Texas Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. ggallick@mdanderson.org.|Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. ggallick@mdanderson.org.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. akaseb@mdanderson.org.
authors.forename: Ahmed O
authors.initials: AO
authors.lastname: Kaseb
authors.affiliation: State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China. ship@ecust.edu.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Shi
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA. hamin@mdanderson.org.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. hamin@mdanderson.org.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D016207:Cytokines / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics*; D051379:Mice; D010766:Phosphorylation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016207:Cytokines; C000597236:IGF1R protein, human; C090444:IK protein, human; D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D014157:Transcription Factors; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1