The RUNX1–PU.1 axis in the control of hematopoiesis

Imperato, Maria Rosaria; Cauchy, Pierre; Obier, Nadine; Bonifer, Constanze

doi:10.1007/s12185-015-1762-8

Cited by 89 publications

(65 citation statements)

References 136 publications

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“…S4C, Upper). Interestingly, both Runx1 and PU.1 are critical for early B-cell development, in part due to their ability to up-regulate the expression of another critical B-cell transcription factor, EBF1 (34,35). However, peaks containing EBF1 consensus sequences are among the most depleted upon Hdac3 deletion (Fig.…”

Section: Cd43mentioning

confidence: 98%

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development

Stengel

Barnett

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Histone deacetylase 3 (HDAC3) is the catalytic component of NCoR/SMRT corepressor complexes that mediate the actions of transcription factors implicated in the regulation of B-cell development and function. We crossed Hdac3 conditional knockout mice with Mb1-Cre knockin animals to delete Hdac3 in early progenitor B cells. The spleens of Hdac3 CD43+ populations identified a defect in V H DJ H recombination with a severe reduction in productive rearrangements, which directly corresponded to the loss of pre-B cells from Hdac3 Δ/− bone marrow. For Hdac3 Δ/− B cells that did show productive VDJ rearrangement, there was significant skewing toward the incorporation of proximal V H gene segments and a corresponding reduction in distal V H gene segment use. Although transcriptional effects within these loci were modest, Hdac3 Δ/− progenitor cells displayed global changes in chromatin structure that likely hindered effective distal V-DJ recombination. Reintroduction of wild-type Hdac3 restored normal B-cell development, whereas an Hdac3 point mutant lacking deacetylase activity failed to complement this defect. Thus, the deacetylase activity of Hdac3 is required for the generation of mature B cells.istone deacetylase 3 (Hdac3) functions as the catalytic component of NCoR/SMRT corepressor complexes that are recruited by sequence-specific transcription factors to regulate transcription through the deacetylation of both histone and nonhistone proteins (1-3). Although bulk histone acetylation is generally controlled during replication by Hdac1 and Hdac2 (4, 5), Hdac3 is required for the maintenance of heterochromatin in some tissues (6, 7). Furthermore, the ability of Hdac3 to modulate chromatin accessibility has profound effects on gene transcription, DNA replication, and DNA repair (8-13). For example, hepatocyte-specific deletion of Hdac3 resulted in global changes in histone acetylation, nucleosomal compaction, and changes in gene expression (6). Although Hdac3 has robust deacetylase activity and is proposed to mediate the activity of some class II HDACs that lack intrinsic deacetylase function (14, 15), deacetylase inactive mutants of Hdac3 appeared to partially complement the phenotype of hepatocyte-specific Hdac3-knockout mice (16). This was interesting given that the livers of Albumin-Cre-Hdac3 −/− mice displayed phenotypes associated with global increases in histone acetylation, including a loss of heterochromatin (6, 9).The adaptive immune system has provided an excellent model for the study of higher-order chromatin structure and also provides a simple genetic system in which to dissect mechanisms of action for Hdac3. Lymphocytes rely on a series of recombinationdependent genome-editing processes, such as VDJ recombination and class-switch recombination, for their development and function. These recombination events are regulated through locus accessibility and require long-range chromatin interactions (17, 18). The Rag1 and Rag2 recombinases introduce DNA doublestrand breaks at recombination signal sequences, fol...

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Section: Cd43mentioning

confidence: 98%

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development

Stengel

Barnett

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…RUNT-related transcription factor 1 (RUNX1), previously named core binding factor A2 (CBFA2) and acute myeloid leukemia 1 (AML1), is a master regulator of hematopoiesis [1]. It is involved in the most frequent chromosome translocations in leukemia (i.e.…”

Section:  Definition Of Runx1 Deficiency/ Fpdmmmentioning

confidence: 99%

“…Upon dimerizing with core binding factor beta (CBFB), RUNX1 binds to promotor regions of several transcription factors like PU.1 regulating their expression [1]. Runx1 binding in GMPs correlates with C/ebpa binding and open chromatin [33].…”

Section:  Functional Properties Of Runx1mentioning

confidence: 99%

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

Schlegelberger

Heller

2017

Seminars in Hematology

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In this review, we discuss disease-causing alterations of RUNT-related transcription factor 1 (RUNX1), a master regulator of hematopoietic differentiation. Familial platelet disorder with predisposition to myeloid leukemia (FPDMM) typically present with 1) mild to moderate thrombocytopenia with normal-sized platelets; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL.Hematological neoplasms in carriers of a germline RUNX1 mutation need additional secondary mutations or chromosome aberrations to develop. If a disease-causing mutation is known in the family, it is important to prevent hematopoietic stem cell transplantation from a sibling or other relative carrying the familial mutation. First experiments introducing a wild-type copy of RUNX1 into iPSC lines from patients with FPDMM appear to demonstrate that by gene correction reversal of the phenotype may be possible.  Definition of RUNX1 deficiency/ FPDMMRUNT-related transcription factor 1 (RUNX1), previously named core binding factor A2 (CBFA2) and acute myeloid leukemia 1 (AML1), is a master regulator of hematopoiesis [1]. It is involved in the most frequent chromosome translocations in leukemia (i.e. t(12;21)/RUNX1/ETV6 in pediatric acute lymphoblastic leukemia, t(8;21)/RUNX1/RUNX1T1 in acute myeloid leukemia (AML), and t(3;21)/RUNX1/EVI1 in therapy-related AML or chronic myeloid leukemia in blast phase [2,3]. Moreover, somatic RUNX1 mutations have recently been identified as recurrent abnormalities in myelodysplastic syndromes (MDS) and AML [4]. These somatic changes are associated with poor prognosis in AML and MDS indicating an increased resistance against exposure to genotoxic agents. RUNX1 mutations seem to trigger progression into MDS and AML in Fanconi anemia and severe congenital neutropenia [5,6]. Song et al. (1999) were the first to describe heterozygous germline RUNX1 mutations in six families, each carrying a different mutation. Individuals carrying germline RUNX1 may be asymptomatic throughout lifetime or develop familial platelet disorder with myeloid malignancies (i.e. FPDMM, OMIM 601399). Characteristic features are 1) mild to moderate thrombocytopenia; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL. There is a great phenotypic heterogeneity. FPDMM is inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity.  Diagnostic criteria to identify persons at riskSince the diagnosis of FPDMM in a patient with leukemia carries important critical implications for the patient and also for her/his family, it is important to recognize clinical features pointing to this genetic predisposition [7]. An important clinical feature is persisting thrombocytopenia or aspirin-like platelet disorder, which are not explained by other reasons.Thorough pedigree analysis may identify first or second degree relatives with bleeding tendency or hematological neoplasms. It has to be kept i...

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“…Each RUNX member has a divergent physiological function. RUNX1 is involved in hematopoiesis [2], RUNX2 is required for bone formation [3], and RUNX3 is associated with gastrointestinal and neuronal development [4, 5]. Therefore, RUNX factors are considered master regulators of multiple phenotypes and signaling pathways in both physiological and pathological conditions, and hence play key roles in many different types of cancer (reviewed in [6–9]).…”

Section: Introductionmentioning

confidence: 99%

RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells

Barutcu

Hong²,

Lajoie

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we examined the relationship between RUNX1-mediated transcription and genome organization. We characterized genome-wide RUNX1 localization and performed RNA-seq and Hi-C in RUNX1-depleted and control MCF-7 breast cancer cells. RNA-seq analysis showed that RUNX1 depletion led to up-regulation of genes associated with chromatin structure and down-regulation of genes related to extracellular matrix biology, as well as NEAT1 and MALAT1 lncRNAs. Our ChIP-Seq analysis supports a prominent role for RUNX1 in transcriptional activation. 30% of all RUNX1 binding sites were intergenic, indicating diverse roles in promoter and enhancer regulation and suggesting additional functions for RUNX1. Hi-C analysis of RUNX1-depleted cells demonstrated that overall three-dimensional genome organization is largely intact, but indicated enhanced association of RUNX1 near Topologically Associating Domain (TAD) boundaries and alterations in long-range interactions. This suggests an architectural role for RUNX1 in fine-tuning local interactions rather than in global organization. Our results provide novel insight into RUNX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNX1-dependent compromised gene expression in breast cancer cells.

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The RUNX1–PU.1 axis in the control of hematopoiesis

Cited by 89 publications

References 136 publications

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells

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