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The most frequently occurring genetic abnormality in pediatric B-ALL 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.
This article was published in the following journal.
Name: Experimental hematology
Hematopoietic stem cells (HSCs) develop in the embryonic aorta-gonad-mesonephros (AGM) region and subsequently relocate to fetal liver. Runx1 transcription factor is essential for HSC development, but...
RUNX1 is a crucial transcription factor for hematological stem cells and well-known for its association with acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). Besides the transl...
Translocations involving the RUNX1 transcription factor gene are frequently identified in leukemia patients, but the partner genes have been characterized in only about half of these cases. We report ...
Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets....
Transcription factor RUNX1 plays a crucial role in hematopoiesis, and its activity is tightly regulated at both transcriptional and post-translational levels. However, translational control of RUNX1 e...
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A widely-expressed protein of approximately 400 to 500 amino acids. Its N-terminal region (DENN domain) interacts with RAB GTP-BINDING PROTEINS and may regulate AUTOPHAGY, as well as PROTEIN TRANSPORT to ENDOSOMES. Expansion of the GGGGCC hexanucleotide repeat in the first intron of the C9orf72 gene is associated with FRONTOTEMPORAL DEMENTIA with AMYOTROPHIC LATERAL SCLEROSIS (FTDALS1).
A transcriptional co-repressor that contains a MYND-type zinc finger (MYND DOMAIN) at its C-terminal and functions as a homo-oligomer. It associates with DNA-binding transcription factors, other repressor proteins, and HISTONE ACETYLTRANSFERASES to repress expression of genes involved in cell growth and differentiation such as MATRIX METALLOPROTEINASE 7 and TCF12. A CHROMOSOMAL TRANSLOCATION involving the RUNX1T1 and CORE BINDING FACTOR ALPHA 2 SUBUNIT (RUNX1) genes frequently occurs in cells of leukemia patients; the resulting fusion protein (AML1-ETO or RUNX1-RUNX1T1) plays a critical role in leukemogenesis.
A regulatory region first identified in the human beta-globin locus but subsequently found in other loci. The region is believed to regulate GENETIC TRANSCRIPTION by opening and remodeling CHROMATIN structure. It may also have enhancer activity.
A transcriptional co-activator for NUCLEAR RECEPTORS. It is characterized by an N-terminal LxxLL sequence, a region that interacts with PPAR GAMMA, and a C-terminal RNA RECOGNITION MOTIF. It increases expression of MITOCHONDRIAL UNCOUPLING PROTEIN to regulate genes involved in metabolic reprogramming in response to dietary restriction and the integration of CIRCADIAN RHYTHMS with ENERGY METABOLISM.
The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.
The process of gene expression is used by eukaryotes, prokaryotes, and viruses to generate the macromolecular machinery for life. Steps in the gene expression process may be modulated, including the transcription, RNA splicing, translation, and post-tran...