HDAC1 Is a Required Cofactor of CBFβ-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia

Richter, Lisa; Wang, Yiqian; Becker, Michelle; Coburn, Rachel A.; Williams, Jacob T.; Amador, Catalina; Hyde, R. Katherine

doi:10.1158/1541-7786.mcr-18-0922

Cited by 11 publications

(17 citation statements)

References 51 publications

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“…Subsequently, Ro5-3335 has been used to inhibit RUNX1 during a variety of pathophysiological processes including, but not exclusively in, macrophages during septic shock, 165 in retinal angiogenesis 173 and, acute myeloid leukaemia. 183 However, direct binding of Ro5-3335 to CBFβ or RUNX has not been well documented, thus whether Ro5-3335 is a direct inhibitor of Runx remains contentious. 184 …”

Section: Runx1 As a Novel Target In Heart Diseasementioning

confidence: 99%

RUNX1: an emerging therapeutic target for cardiovascular disease

Riddell

McBride

Braun

et al. 2020

Cardiovascular Research

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Runt-related transcription factor-1 (RUNX1), also known as acute myeloid leukaemia 1 protein (AML1), is a member of the core-binding factor family of transcription factors which modulate cell proliferation, differentiation, and survival in multiple systems. It is a master-regulator transcription factor, which has been implicated in diverse signalling pathways and cellular mechanisms during normal development and disease. RUNX1 is best characterized for its indispensable role for definitive haematopoiesis and its involvement in haematological malignancies. However, more recently RUNX1 has been identified as a key regulator of adverse cardiac remodelling following myocardial infarction. This review discusses the role RUNX1 plays in the heart and highlights its therapeutic potential as a target to limit the progression of adverse cardiac remodelling and heart failure.

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Section: Runx1 As a Novel Target In Heart Diseasementioning

confidence: 99%

RUNX1: an emerging therapeutic target for cardiovascular disease

Riddell

McBride

Braun

et al. 2020

Cardiovascular Research

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“…Recent results suggest that HDAC1 is an important component of the AML1/CBFβ-SMMHC fusion complex, which functions to activate transcription of specific target genes. The authors found that in vivo treatment with the HDAC1 inhibitor induced differentiation and apoptosis of leukemia cells, indicating HDAC1 as a potential therapeutic target [59]. These findings suggest an important role for CBFβ-SMMHC in regulating the expression of genes essential for emergence of the hematopoietic stem cell [60].…”

Section: Leukemia Triggered By Cbfβ-myh11mentioning

confidence: 97%

Core Binding Factor Leukemia: Chromatin Remodeling Moves Towards Oncogenic Transcription

Beghini

2019

Cancers

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Acute myeloid leukemia (AML), the most common acute leukemia in adults, is a heterogeneous malignant clonal disorder arising from multipotent hematopoietic progenitor cells characterized by genetic and concerted epigenetic aberrations. Core binding factor-Leukemia (CBFL) is characterized by the recurrent reciprocal translocations t(8;21)(q22;q22) or inv(16)(p13;q22) that, expressing the distinctive RUNX1-RUNX1T1 (also known as Acute myeloid leukemia1-eight twenty-one, AML1-ETO or RUNX1/ETO) or CBFB-MYH11 (also known as CBFβ-SMMHC) translocation product respectively, disrupt the essential hematopoietic function of the CBF. In the past decade, remarkable progress has been achieved in understanding the structure, three-dimensional (3D) chromosomal topology, and disease-inducing genetic and epigenetic abnormalities of the fusion proteins that arise from disruption of the CBF subunit alpha and beta genes. Although CBFLs have a relatively good prognosis compared to other leukemia subtypes, 40–50% of patients still relapse, requiring intensive chemotherapy and allogenic hematopoietic cell transplantation (alloHCT). To provide a rationale for the CBFL-associated altered hematopoietic development, in this review, we summarize the current understanding on the various molecular mechanisms, including dysregulation of Wnt/β-catenin signaling as an early event that triggers the translocations, playing a pivotal role in the pathophysiology of CBFL. Translation of these findings into the clinical setting is just beginning by improvement in risk stratification, MRD assessment, and development of targeted therapies.

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“…For example, HDAC7 regulates the acetylation of H3K27 and the transcriptional activity of super-enhancer-related genes in breast cancer stem cells ( 80 ). A common mutation in AML is a chromosome 16 inversion that fuses the core-binding factor beta (CBFB) gene with the smooth muscle myosin heavy chain gene (MYH11) to form the oncogene CBFB-MYH11 ( 61 ). The expressed protein CBFbeta-SMMHC forms a heterodimer with the key hematopoietic transcription factor RUNX1, and CBFbeta-SMMHC acts together with RUNX1 to activate the transcription of specific target genes ( 61 ).…”

Section: The Components and Process Of Acetylation System In Cancersmentioning

confidence: 99%

The role of protein acetylation in carcinogenesis and targeted drug discovery

2022

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Protein acetylation is a reversible post-translational modification, and is involved in many biological processes in cells, such as transcriptional regulation, DNA damage repair, and energy metabolism, which is an important molecular event and is associated with a wide range of diseases such as cancers. Protein acetylation is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) in homeostasis. The abnormal acetylation level might lead to the occurrence and deterioration of a cancer, and is closely related to various pathophysiological characteristics of a cancer, such as malignant phenotypes, and promotes cancer cells to adapt to tumor microenvironment. Therapeutic modalities targeting protein acetylation are a potential therapeutic strategy. This article discussed the roles of protein acetylation in tumor pathology and therapeutic drugs targeting protein acetylation, which offers the contributions of protein acetylation in clarification of carcinogenesis, and discovery of therapeutic drugs for cancers, and lays the foundation for precision medicine in oncology.

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HDAC1 Is a Required Cofactor of CBFβ-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia

Abstract: Implications: This report describes a novel role for HDAC1 as a cofactor for the leukemogenic fusion protein CBFb-SMMHC and shows that inhibitors of HDAC1 effectively target leukemia cells expressing the fusion protein in vivo.

Cited by 11 publications

References 51 publications

RUNX1: an emerging therapeutic target for cardiovascular disease

RUNX1: an emerging therapeutic target for cardiovascular disease

Core Binding Factor Leukemia: Chromatin Remodeling Moves Towards Oncogenic Transcription

The role of protein acetylation in carcinogenesis and targeted drug discovery

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