ZFIN ID: ZDB-PUB-161229-2
Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia
Liau, W.S., Tan, S.H., Ngoc, P.C., Wang, C.Q., Tergaonkar, V., Feng, H., Gong, Z., Osato, M., Look, A.T., Sanda, T.
Date: 2017
Source: Leukemia   31(8): 1798-1807 (Journal)
Registered Authors: Gong, Zhiyuan, Liau, Wei-Siang, Look, A. Thomas, Sanda, Takaomi
Keywords: none
MeSH Terms:
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors/physiology*
  • Cell Line, Tumor
  • Enhancer Elements, Genetic/physiology*
  • GTP-Binding Proteins/genetics*
  • Humans
  • Membrane Proteins/genetics*
  • Mice
  • Mice, Inbred C57BL
  • Multigene Family
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/etiology*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
  • Proto-Oncogene Proteins/physiology*
  • Transcription Factors/physiology*
  • Zebrafish
PubMed: 28028313 Full text @ Leukemia
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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.Leukemia accepted article preview online, 28 December 2016. doi:10.1038/leu.2016.392.
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