Journal
LEUKEMIA
Volume 31, Issue 8, Pages 1798-1807Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.392
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Funding
- National Research Foundation, Prime Minister's Office, Singapore, under its Competitive Research Programme [NRF-NRFF2013-02]
- National Medical Research Council
- Singapore Ministry of Health [NMRC/CIRG/1443/2016]
- US National Cancer Institute [1K99CA157951]
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiative
- Grants-in-Aid for Scientific Research [16K14613, 15H04312] Funding Source: KAKEN
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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.
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