title: Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia.
abstract: The transcription factor TAL1/SCL is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1-regulated super-enhancer controlling the GIMAP locus, which resides within an insulated chromosomal locus in T-ALL cells. The GIMAP genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The GIMAP enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human GIMAP genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the GIMAP enhancer contributes to T-cell leukemogenesis.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore.
authors.forename: W S
authors.initials: WS
authors.lastname: Liau
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore.
authors.forename: S H
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore.
authors.forename: P C T
authors.initials: PCT
authors.lastname: Ngoc
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore.|Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: C Q
authors.initials: CQ
authors.lastname: Wang
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Tergaonkar
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Cancer Research Center, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: H
authors.identifier: 0000-0003-1318-821X
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
authors.forename: Z
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore.
authors.forename: M
authors.initials: M
authors.lastname: Osato
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Look
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: T
authors.identifier: 0000-0003-1621-4954
authors.initials: T
authors.lastname: Sanda
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D005810:Multigene Family; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000502:physiology*; D015027:Zebrafish
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019204:GTP-Binding Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C450435:GIMAP1 protein, human; C067143:TAL1 protein, human