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A frameshift variant in the specificity protein 1 triggers superactivation of Sp1-mediated transcription in familial bone marrow failure

ABSTRACT: Inherited bone marrow failure (BMF) syndromes are a heterogeneous group of diseases characterised by defective hematopoiesis and often predispose to myelodysplastic syndrome (MDS) and acute myeloid leukemia. We have studied a large family consisting of several affected individuals with hematological abnormalities including one family member who died of acute leukemia. By whole exome sequencing, we identified a novel frameshift variant in the ubiquitously expressed transcription factor specificity protein 1 SP1). This heterozygous variant (c.1995delA) truncates the canonical Sp1 molecule in the highly conserved C-terminal DNA binding zinc finger domains. Functional characterisation of the truncated Sp1 molecule revealed compromised DNA binding ability and educed stability. Transcriptomic analysis and gene promoter characterisation in patients’ blood revealed a hypermorphic effect of this Sp1 variant, triggering superactivation of Sp1-mediated transcription and driving a significant upregulation of Sp1 target genes. his familial genetic study indicates a central role for Sp1 in causing autosomal dominant transmission of BMF, thereby confirming its critical role in hematopoiesis in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152262 | GEO | 2020/06/12

REPOSITORIES: GEO

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The cell-nonautonomous function of ID1 supports AML progression from the microenvironment via ANGPLT7

Project description:Bone marrow microenvironment (BMM) can maintain and regulate HSC and LSC via secreted components or direct interaction. Increasing evidence indicates that dissecting and targeting BMM-driven mechanisms of LSC might provide key adjuvant therapies to eradicate leukemia. ID1, a key transcriptional regulator in LSC previously identified by us, controls cytokine/chemokine production in the BMM, but the role of ID1 in AML-BMM remains obscure. Here, we report that ID1 is highly expressed in AML-BMM, especially in bone marrow mesenchymal stem cell (BMSC), and deletion of Id1 in BMM resulted in impaired AML progression in AML mouse model. Mechanistically, we found that Id1 deficiency markedly reduced the protein level of SP1 in mesenchymal cells co-cultured with AML cells. Through Id1-interactome analysis, we discovered Id1 interacts with Rnf4, the ubiquitin E3 ligase, and led to decreased Sp1 degradation. Disrupting ID1-RNF4 interaction by truncates in mesenchymal cells significantly decreased SP1 protein level and retarded the AML cell proliferation. We identified the target of Sp1, Angptl7, was the primary differentially expression protein factor in Id1-/- bone marrow supernatant fluid (BMSF) to regulate AML progression in mice. Taken together, our study highlights the critical role of ID1 in AML-BMM and assists development of diagnostic/therapeutic strategies for AML.

2023-10-04 | GSE219049 | GEO

In Fanconi Anemia, impaired accumulation of bone marrow neutrophils during emergency granulopoiesis induces hematopoietic stem cell stress

Project description:Fanconi Anemia (FA) is an inherited disorder of DNA-repair caused by mutation in one of 20+ interrelated genes that repair intra-strand DNA crosslinks and rescue collapsed or stalled replication forks. The most common hematologic abnormality in FA is anemia, but progression to bone marrow failure (BMF), clonal hematopoiesis, or acute myeloid leukemia (AML) may also occur. In prior studies, we found that Fanconi DNA-repair is required for successful emergency granulopoiesis; the process for rapid neutrophil production during the innate immune response. Specifically, Fancc-/- mice did not develop neutrophilia in response to emergency granulopoiesis stimuli, but instead exhibited apoptosis of bone marrow hematopoietic stem cells (HSCs) and differentiating neutrophils. Repeated emergency granulopoiesis challenges induced BMF in most Fancc-/- mice, with AML in survivors. In contrast, we found equivalent emergency granulopoiesis-induced neutrophilia in Fancc-/-Tp53+/- mice and wild type (WT) mice, without BMF in either. Since bone marrow neutrophil accumulation triggers termination of emergency granulopoiesis, we hypothesize neutrophilia protects Fancc-/-Tp53+/- bone marrow from the stress of sustained inflammatory physiology, as experienced by Fancc-/- mice.

2024-08-28 | GSE267161 | GEO

Expression data of human mesenchymal stromal cells isolated from bone marrow of ML-DS, AMKL patients and HD

Project description:Bone marrow fibrosis (BMF) is a rare complication in acute leukemia. In pediatrics, it predominantly occurs in acute megakaryoblastic leukemia (AMKL) and here especially in patients with trisomy 21, called myeloid leukemia in Down syndrome (ML-DS). Defects in mesenchymal stromal cells (MSCs) and cytokines specifically released by the myeloid blasts are the main drivers of fibrosis in the bone marrow niche (BMN). In order to determine which factors are necessary/sufficient for the BMF, we first established MSCs from pediatric patients with AMKL and ML-DS. Healthy donor (HD) control MSCs were established from children and adolescents ≤18 years of age. Steady-state analyses of the MSCs revealed that patient-derived MSCs exhibited decreased adipogenic differentiation potential, enrichment of proliferation-associated genes and upregulation of the oncofetal protein IF2B3. TGFB1 exposure in vitro promoted early profibrotic changes in all three MSC entities. To study BMF induction for longer periods of time, we created an in vivo humanized artificial BMN in immunodeficient mice. Injection of AMKL blasts as producers of TGFB1 specifically induced fibrosis grade I/II in a dose-dependent fashion, thus strongly suggesting TGFB1 excess to be sufficient for BMF. Our in vivo BMF model will be instrumental to specifically prevent the BMF and to identify potentially druggable target genes. We used microarrays to obtain a global overview of the differences between undifferentiated ML-DS- and AMKL-MSC compared to HD-MSC

2020-07-27 | GSE138861 | GEO

A crucial role of the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification [ChIP-Seq]

Project description:Mammalian development is regulated by the interplay of tissue-specific and ubiquitously expressed transcription factors, such as Sp1. Sp1 knock-out mice die in utero with multiple phenotypic aberrations, but the underlying molecular mechanism of this differentiation failure has been elusive. Here we used conditional knock-out mice as well as the differentiation of mouse ES cells as a model to address this issue. To this end we examined differentiation potential, global gene expression patterns and Sp1 target regions in Sp1 wild-type and deficient cells representing different stages of hematopoiesis. Sp1-/- cells progress through most embryonic stages of blood cell development but cannot complete terminal differentiation. For most Sp1 target and non-target genes, gene expression is unaffected by Sp1 inactivation. However, Cdx and multiple Hox genes are stage-specific targets of Sp1 and are down-regulated at an early stage. As a consequence, expression of genes involved in hematopoietic specification are progressively deregulated, highlighting the regulatory hierarchy of hematopoietic specification. Our work demonstrates that the early absence of active Sp1 sets a cascade in motion that culminates in a failure of terminal hematopoietic differentiation and emphasizes the role of ubiquitously expressed transcription factors for tissue-specific gene regulation. Two ChIP-Seq data from Sp1 transcription factor obtained from FLK+ and progenitor cells

2014-06-12 | E-GEOD-52496 | biostudies-arrayexpress

Study of Covalent Menin Inhibitor BMF-219 in Adult Patients With KRAS Driven Non-Small Cell Lung Cancer, Pancreatic Cancer, and Colorectal Cancer

Project description:A Phase 1/1b dose finding study to determine the OBD(s) and RP2D(s) of BMF-219, a covalent menin inhibitor small molecule, in subjects with KRAS mutated unresectable, locally advanced, or metastatic NSCLC (Cohort 1), PDAC (Cohort 2), and CRC (Cohort 3).

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A crucial role of the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification [array]

Project description:Mammalian development is regulated by the interplay of tissue-specific and ubiquitously expressed transcription factors, such as Sp1. Sp1 knock-out mice die in utero with multiple phenotypic aberrations, but the underlying molecular mechanism of this differentiation failure has been elusive. Here we used conditional knock-out mice as well as the differentiation of mouse ES cells as a model to address this issue. To this end we examined differentiation potential, global gene expression patterns and Sp1 target regions in Sp1 wild-type and deficient cells representing different stages of hematopoiesis. Sp1-/- cells progress through most embryonic stages of blood cell development but cannot complete terminal differentiation. For most Sp1 target and non-target genes, gene expression is unaffected by Sp1 inactivation. However, Cdx and multiple Hox genes are stage-specific targets of Sp1 and are down-regulated at an early stage. As a consequence, expression of genes involved in hematopoietic specification are progressively deregulated, highlighting the regulatory hierarchy of hematopoietic specification. Our work demonstrates that the early absence of active Sp1 sets a cascade in motion that culminates in a failure of terminal hematopoietic differentiation and emphasizes the role of ubiquitously expressed transcription factors for tissue-specific gene regulation. Microarray expression data, 16 arrays with 2 independent biological replicates (8 arrays wildtype and 8 arrays knock out) obtained from differentiation of ES cells to study the transcription factor Sp1 activity at early stages of early hematopoietic specification.

2014-06-12 | E-GEOD-52497 | biostudies-arrayexpress

Robust hematopoietic specification requires the ubiquitous Sp1 and Sp3 transcription factors [RNA-seq]

Project description:Development requires the cooperation of tissue-specific and ubiquitously expressed transcription factors, such as Sp-family members. However, the molecular details of how ubiquitous factors participate in developmental processes are still unclear. We previously showed that during the differentiation of embryonic stem cells lacking Sp1 DNA binding activity (Sp1deltaDBD/deltaDBD cells), early blood progenitors are formed. However, gene expression during differentiation becomes progressively deregulated and terminal differentiation is severely compromised. Here we studied the cooperation of Sp1 and its closest paralogue Sp3 in hematopoietic development and demonstrate that Sp1 and Sp3 binding sites largely overlap. Sp3 cooperates with Sp1deltaDBD/deltaDBD but is unable to support hematopoiesis in the complete absence of Sp1. Using single cell gene expression analysis, we show that the lack of Sp1 DNA binding leads to a distortion of cell fate decision timing, indicating that stable chromatin bi nding of Sp1 is required to maintain robust differentiation trajectories.

2019-06-06 | GSE126500 | GEO

Robust hematopoietic specification requires the ubiquitous Sp1 and Sp3 transcription factors [ChIP-seq]

2019-06-06 | GSE126496 | GEO

Robust hematopoietic specification requires the ubiquitous Sp1 and Sp3 transcription factors [ATAC-Seq]

2019-06-06 | GSE126493 | GEO

Robust hematopoietic specification requires the ubiquitous Sp1 and Sp3 transcription factors

Project description:Development requires the cooperation of tissue-specifically and ubiquitously expressed transcription factors, such as Sp-family members. However, the molecular details of how ubiquitous factors participate in developmental processes are still unclear. We previously showed that during the differentiation of embryonic stem cells lacking Sp1 DNA binding activity (Sp1DDBD/DDBD cells), early blood progenitors are formed. However, gene expression during differentiation becomes progressively deregulated and terminal differentiation is blocked. Here we studied the cooperation of Sp1 and its homologue Sp3 in hematopoietic development and demonstrate that Sp1 and Sp3 binding sites largely overlap. Sp3 cooperates with Sp1DDBD/DDBD cells but is unable to support hematopoiesis in the complete absence of Sp1. Using single cell gene expression analysis, we show that the lack of Sp1 DNA binding leads to a distortion of cell fate decision timing, indicating that stable chromatin binding of Sp1 is required to maintain robust differentiation trajectories.

2019-06-04 | GSE126497 | GEO

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