The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid–induced myeloid gene expression and differentiation in acute myeloid leukemia

Abstract

<jats:p>CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3, also known as MTG16 or ETO2) is a myeloid translocation gene family protein that functions as a master transcriptional corepressor in hematopoiesis. Recently, it has been shown that CBFA2T3 maintains leukemia stem cell gene expression and promotes relapse in acute myeloid leukemia (AML). However, a role for CBFA2T3 in myeloid differentiation of AML has not been reported. Here, we show that CBFA2T3 represses retinoic acid receptor (RAR) target gene expression and inhibits all-<jats:italic>trans</jats:italic>-retinoic acid (ATRA)-induced myeloid differentiation of AML cells. ChIP-Seq revealed that CBFA2T3 targets the RARα/RXRα cistrome in U937 AML cells, predominantly at myeloid-specific enhancers associated with terminal differentiation. CRISPR/Cas9-mediated abrogation of CBFA2T3 resulted in spontaneous and ATRA-induced activation of myeloid-specific genes in a manner correlated with myeloid differentiation. Importantly, these effects were reversed by CBFA2T3 re-expression. Mechanistic studies showed that CBFA2T3 inhibits RAR target gene transcription by acting at an early step to regulate histone acetyltransferase recruitment, histone acetylation, and chromatin accessibility at RARα target sites, independently of the downstream, RAR-mediated steps of transcription. Finally, we validated the inhibitory effect of CBFA2T3 on RAR in multiple AML subtypes and patient samples. To our knowledge, this is the first study to show that CBFA2T3 down-regulation is both necessary and sufficient for enhancing ATRA-induced myeloid gene expression and differentiation of AML cells. Our findings suggest that CBFA2T3 can serve as a potential target for enhancing AML responsiveness to ATRA differentiation therapies.</jats:p>

Population Genomic Sequencing Delineates Global Landscape of Copy Number Variations that Drive Domestication and Breed Formation of in Chicken

“…At least ten genes were found to participate in the pathways of inflammatory and immune response. CBFA2T3 , a factor in human acute myeloid leukemia, promotes myeloid differentiation ( Steinauer et al, 2020 ). In cattle, this gene is found under selection pressure, which might be related to physiological adaptations to the environment and disease resistance ( Ben-Jemaa et al, 2020 ).…”

EGCG Prevents the Transcriptional Reprogramming of an Inflammatory and Immune-Suppressive Molecular Signature in Macrophage-like Differentiated Human HL60 Promyelocytic Leukemia Cells

“…The rapid expansion of short-term stem cells, multipotent progenitor cells, and megakaryocyte-erythroid progenitor cells, which are necessary during hematopoietic stress/emergency, is hampered by Mtg16 gene inactivation [ 35 ]. According to a number of studies, CBFA2T3 inhibits differentiation and enhances proliferation in a range of hematopoietic cell types [ 59 , 60 , 61 , 62 ]. Targeting CBFA2T3 in leukemia, especially acute lymphoblastic leukemia that expresses the E2A-Pbx1 fusion protein, is also supported by an increasing body of evidence [ 58 , 62 , 63 ].…”

The high-performance technology CRISPR/Cas9 improves knowledge and management of acute myeloid leukemia

“…CBFA2T3 inhibits the early step of RAR target gene transcription and could be a new target to improve AML cell differentiation induced by ATRA (ref. 19 ).…”