PUBLICATION

ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis

Authors

Leong, W.Z., Tan, S.H., Ngoc, P.C.T., Amanda, S., Yam, A.W.Y., Liau, W.S., Gong, Z., Lawton, L.N., Tenen, D.G., Sanda, T.

ID

ZDB-PUB-180113-14

Date

2018

Source

Genes & Development 31(23-24): 2343-2360 (Journal)

Registered Authors

Gong, Zhiyuan, Liau, Wei-Siang, Sanda, Takaomi

Keywords

ARID5B, MYC, T-cell acute lymphoblastic leukemia, TAL1, core regulatory circuit

MeSH Terms

Cell Survival/genetics
Humans
Carcinogenesis/genetics*
Thymus Gland/growth & development
Gene Expression Regulation, Neoplastic*
Cell Line, Tumor
Protein Domains/genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
DNA-Binding Proteins/genetics
DNA-Binding Proteins/metabolism*
Enhancer Elements, Genetic/genetics
HEK293 Cells
Zebrafish
T-Cell Acute Lymphocytic Leukemia Protein 1/metabolism*
Animals
Genes, myc/genetics
Transcriptional Activation/genetics
Thymocytes/metabolism
Protein Binding
Transcription Factors/genetics
Transcription Factors/metabolism*
Gene Expression Profiling

(all 22)

PubMed

29326336 Full text @ Genes & Dev.

Abstract

The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B (ARID5B) as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2-4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells. The enhancer located 135 kb upstream of the ARID5B gene locus is activated under a superenhancer in T-ALL cells but not in normal T cells. Notably, ARID5B-bound regions are associated predominantly with active transcription. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. ARID5B positively regulates the expression of TAL1 and its regulatory partners. ARID5B also activates the expression of the oncogene MYC Importantly, ARID5B is required for the survival and growth of T-ALL cells, and forced expression of ARID5B in immature thymocytes results in thymus retention, differentiation arrest, radioresistance, and tumor formation in zebrafish. Our results indicate that ARID5B reinforces the oncogenic transcriptional program by positively regulating the TAL1-induced regulatory circuit and MYC in T-ALL, thereby contributing to T-cell leukemogenesis.

Genes / Markers

Figures

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Expression

Fish	Conditions	Stage	Anatomy	Assay	Figure
ns102Tg	standard conditions	Adult	thymus	RTPCR	Fig. 7
ns102Tg	standard conditions	Adult	thymus	RTPCR	Fig. 7
ns102Tg	standard conditions	Adult	thymus	RTPCR	Fig. 7
ns102Tg	particle radiation	Adult	thymus	IFL	Fig. 7
ns102Tg	standard conditions	Adult	thymus	RTPCR	Fig. 7
ns102Tg	standard conditions	Adult	thymus	RTPCR	Fig. 7
ns102Tg	standard conditions	Adult	thymus	RTPCR	Fig. 7

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
ns102Tg	standard conditions	Days 45-89	thymus increased size, abnormal	Fig. 7
ns102Tg	standard conditions	Adult	thymus cd4-1 expression decreased amount, abnormal	Fig. 7
ns102Tg	standard conditions	Adult	thymus cd8a expression decreased amount, abnormal	Fig. 7
ns102Tg	standard conditions	Adult	thymus lck expression decreased amount, abnormal	Fig. 7
ns102Tg	standard conditions	Adult	thymus myca expression increased amount, abnormal	Fig. 7
ns102Tg	standard conditions	Adult	thymus mycb expression increased amount, abnormal	Fig. 7
ns102Tg	standard conditions	Adult	thymus trac expression decreased amount, abnormal	Fig. 7
ns102Tg	standard conditions	Adult	thymus increased size, abnormal	Fig. 7
ns102Tg	standard conditions	Adult	thymus precursor T-cell lymphoblastic lymphoma/leukaemia present, abnormal	Fig. 7

1 - 9 of 9

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ns102Tg	Tg(rag2:Hsa.ARID5B) Tg3(rag2:mCherry)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
obsolete T-cell lymphoblastic leukemia/lymphoma			TAS

Sequence Targeting Reagents

Fish

Fish
ns102Tg

Antibodies

Orthology

Gene	Orthology
arid5b

Engineered Foreign Genes

Marker	Marker Type	Name
mCherry	EFG	mCherry

Mapping

Leong et al., 2018 ZDB-PUB-180113-14 PMID:29326336

ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis

Leong et al., 2018

ZDB-PUB-180113-14
PMID:29326336