PUBLICATION
Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia
- Authors
- 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.
- ID
- ZDB-PUB-161229-2
- 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
-
- Humans
- Mice
- Basic Helix-Loop-Helix Transcription Factors/physiology*
- Zebrafish
- Transcription Factors/physiology*
- Mice, Inbred C57BL
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/etiology*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
- Multigene Family
- Membrane Proteins/genetics*
- Enhancer Elements, Genetic/physiology*
- Proto-Oncogene Proteins/physiology*
- Cell Line, Tumor
- Animals
- GTP-Binding Proteins/genetics*
- PubMed
- 28028313 Full text @ Leukemia
Citation
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. (2017) Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Leukemia. 31(8):1798-1807.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping