Liau WS1, Tan SH1, Ngoc PC1, Wang CQ1,2, Tergaonkar V2,3,4, Feng H5, Gong Z6, Osato M1, Look AT7,8, Sanda T1,9.
1 Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore.
2 Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
4 Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
5 Department of Pharmacology and Experimental Therapeutics, Cancer Research Center, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
6 Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
7 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
8 Division of Hematology/Oncology, Children’s Hospital, Boston, MA, USA.
9 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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.