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ETV6-RUNX1 interacts with a region in SPIB intron 1 to regulate gene expression in pre-B-cell acute lymphoblastic leukemia
- Source :
- Experimental Hematology. 73:50-63.e2
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- The most frequently occurring genetic abnormality in pediatric B-lymphocyte-lineage acute lymphoblastic leukemia is the t(12;21) chromosomal translocation that results in a ETV6-RUNX1 (also known as TEL-AML1) fusion gene. Expression of ETV6-RUNX1 induces a preleukemic condition leading to acquisition of secondary driver mutations, but the mechanism is poorly understood. SPI-B (encoded by SPIB) is an important transcriptional activator of B-cell development and differentiation. We hypothesized that SPIB is directly transcriptionally repressed by ETV6-RUNX1. Using chromatin immunoprecipitation, we identified a regulatory region in the first intron of SPIB that interacts with ETV6-RUNX1. Mutation of the RUNX1 binding site in SPIB intron 1 prevented transcriptional repression in transient transfection assays. Next, we sought to determine to what extent gene expression in REH cells can be altered by ectopic SPI-B expression. SPI-B expression was forced using CRISPR-mediated gene activation and also using a retroviral vector. Forced expression of SPI-B resulted in altered gene expression and, at high levels, impaired cell proliferation and induced apoptosis. Finally, we identified CARD11 and CDKN1A (encoding p21) as transcriptional targets of SPI-B involved in regulation of proliferation and apoptosis. Taken together, this study identifies SPIB as an important target of ETV6-RUNX1 in regulation of B-cell gene expression in t(12;21) leukemia.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
0301 basic medicine
Cancer Research
Oncogene Proteins, Fusion
Chromosomes, Human, Pair 21
CARD11
Apoptosis
Biology
Response Elements
medicine.disease_cause
Translocation, Genetic
Fusion gene
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Line, Tumor
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
hemic and lymphatic diseases
Gene expression
Genetics
medicine
Humans
Molecular Biology
Cell Proliferation
Regulation of gene expression
Mutation
Chromosomes, Human, Pair 12
Gene Expression Regulation, Leukemic
Intron
Cell Biology
Hematology
Introns
Cell biology
CARD Signaling Adaptor Proteins
DNA-Binding Proteins
030104 developmental biology
RUNX1
chemistry
Guanylate Cyclase
030220 oncology & carcinogenesis
Core Binding Factor Alpha 2 Subunit
Chromatin immunoprecipitation
Transcription Factors
Subjects
Details
- ISSN :
- 0301472X
- Volume :
- 73
- Database :
- OpenAIRE
- Journal :
- Experimental Hematology
- Accession number :
- edsair.doi.dedup.....51247e056f5baeebb9c1b4e7eb13ba13