In vivo conditional deletion of HDAC7 reveals its requirement to establish proper B lymphocyte identity and development

Azagra, Alba; Román-González, Lidia; Collazo, Olga; Rodríguez-Ubreva, Javier; Yébenes, Virginia G. de; Barneda-Zahonero, Bruna; Rodríguez, Jairo; Moura, Manuel Castro de; Grego-Bessa, Joaquím; Fernández-Duran, Irene; Islam, Abul B.M.M.K.; Esteller, Manel; Ramiro, Almudena R.; Ballestar, Esteban; Parra, Maribel

doi:10.1084/jem.20150821

Cited by 40 publications

(27 citation statements)

References 29 publications

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“…In particular, HDAC7 is frequently underexpressed in pro-B-ALL and Burkitt lymphoma. Ectopically expressed HDAC7 interacts with the MEF2C-HDAC3-SMRT complex and suppresses c-Myc expression in both MEF2C-and self-catalytic activitydependent manners [61,77,78]. Conversely, HDAC7 appears to overexpressed in pre-B-ALL t (9;22), B-ALL t (8;14), ALL t (12;21) and T-ALL ( Fig.…”

Section: B Cellmentioning

confidence: 94%

“…The terminal differentiation of lymphoid lineages originates from common lymphoid progenitors (CLPs), which can be further divided into all-lymphoid progenitors (ALPs) and B cell-biased lymphoid progenitors (BLPs). ALPs retain the potential to generate B cells, T cells, natural killer cells and lymphoid dendritic cells, whereas BLPs are biased toward pre-B cells and immature B cells, and the latter migrate to the spleen to complete their maturation [59][60][61] (Fig. 2).…”

Section: Lymphocyte Lineages Terminal Differentiationmentioning

confidence: 99%

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Role of HDACs in normal and malignant hematopoiesis

2020

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Normal hematopoiesis requires the accurate orchestration of lineage-specific patterns of gene expression at each stage of development, and epigenetic regulators play a vital role. Disordered epigenetic regulation has emerged as a key mechanism contributing to hematological malignancies. Histone deacetylases (HDACs) are a series of key transcriptional cofactors that regulate gene expression by deacetylation of lysine residues on histone and nonhistone proteins. In normal hematopoiesis, HDACs are widely involved in the development of various lineages. Their functions involve stemness maintenance, lineage commitment determination, cell differentiation and proliferation, etc. Deregulation of HDACs by abnormal expression or activity and oncogenic HDAC-containing transcriptional complexes are involved in hematological malignancies. Currently, HDAC family members are attractive targets for drug design, and a variety of HDAC-based combination strategies have been developed for the treatment of hematological malignancies. Drug resistance and limited therapeutic efficacy are key issues that hinder the clinical applications of HDAC inhibitors (HDACis). In this review, we summarize the current knowledge of how HDACs and HDAC-containing complexes function in normal hematopoiesis and highlight the etiology of HDACs in hematological malignancies. Moreover, the implication and drug resistance of HDACis are also discussed. This review presents an overview of the physiology and pathology of HDACs in the blood system.

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Section: B Cellmentioning

confidence: 94%

Section: Lymphocyte Lineages Terminal Differentiationmentioning

confidence: 99%

Role of HDACs in normal and malignant hematopoiesis

2020

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“…Only 8 loci, among the 155 analysed, showed enriched peaks for HDAC7 in regions close to the TSS. It is possible that the deacetylase binds other regulative elements located more distally, with respect to the TSS (Azagra et al, 2016). Indeed, the genomic distribution of HDAC7 peaks evinced that approx.…”

Section: Mapping Hdac7 Activities At the Genomic Levelmentioning

confidence: 99%

“…This plasticity holds remarkably true for HDAC7. Genetic studies in mice have proved that Hdac7 controls vascular stability and remodelling (Chang et al, 2006), as well as B-cell and T-cell development (Azagra et al, 2016;Kasler and Verdin, 2007;Navarro et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

et al. 2019

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HDAC7 is a pleiotropic transcriptional coregulator that controls different cellular fates. Here, we demonstrate that in human mammary epithelial cells, HDAC7 sustains cell proliferation and favours a population of stem‐like cells, by maintaining a proficient microenvironment. In particular, HDAC7 represses a repertoire of cytokines and other environmental factors, including elements of the insulin‐like growth factor signalling pathway, IGFBP6 and IGFBP7. This HDAC7‐regulated secretome signature predicts negative prognosis for luminal A breast cancers. ChIP‐seq experiments revealed that HDAC7 binds locally to the genome, more frequently distal from the transcription start site. HDAC7 can colocalize with H3K27‐acetylated domains and its deletion further increases H3K27ac at transcriptionally active regions. HDAC7 levels are increased in RAS‐transformed cells, in which this protein was required not only for proliferation and cancer stem‐like cell growth, but also for invasive features. We show that an important direct target of HDAC7 is IL24 , which is sufficient to suppress the growth of cancer stem‐like cells.

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“…Studies conducted by Azagra et al [24] explored the potential role of HDAC7 in B cell development by generating a conditional knockout mouse model. The deletion of HDAC7 induces lymphopenia in peripheral organs secondary to the arrest of early B cell development.…”

Section: Hdac Classification and Their Physiological Rolesmentioning

confidence: 99%

The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease

Cosenza

Pozzi

2018

IJMS

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Histone deacetylases (HDACs) are master regulators of chromatin remodeling, acting as epigenetic regulators of gene expression. In the last decade, inhibition of HDACs has become a target for specific epigenetic modifications related to cancer development. Overexpression of HDAC has been observed in several hematologic malignancies. Therefore, the observation that HDACs might play a role in various hematologic malignancies has brought to the development of HDAC inhibitors as potential antitumor agents. Recently, the class IIb, HDAC6, has emerged as one potential selective HDACi. This isoenzyme represents an important pharmacological target for selective inhibition. Its selectivity may reduce the toxicity related to the off-target effects of pan-HDAC inhibitors. HDAC6 has also been studied in cancer especially for its ability to coordinate a variety of cellular processes that are important for cancer pathogenesis. HDAC6 has been reported to be overexpressed in lymphoid cells and its inhibition has demonstrated activity in preclinical and clinical study of lymphoproliferative disease. Various studies of HDAC6 inhibitors alone and in combination with other agents provide strong scientific rationale for the evaluation of these new agents in the clinical setting of hematological malignancies. In this review, we describe the HDACs, their inhibitors, and the recent advances of HDAC6 inhibitors, their mechanisms of action and role in lymphoproliferative disorders.

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In vivo conditional deletion of HDAC7 reveals its requirement to establish proper B lymphocyte identity and development

Abstract: The histone deacetylase HDAC7 interacts with and represses myeloid and T cell genes in pro–B cells. HDAC7 deletion blocks early B cell development and results in severe lymphopenia.

Cited by 40 publications

References 29 publications

Role of HDACs in normal and malignant hematopoiesis

Role of HDACs in normal and malignant hematopoiesis

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease

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