Biology subjects

Touw, I. P.

Publications and source records attributed to Touw, I. P..

5 recordsLinked to original sources

bioRxiv2024

Hematological phenotypes in GATA2 deficiency syndrome arise from secondary injuries and maladaptation to proliferation

The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the GATA2 gene drive severe hematologic abnormalities and are associated with an increased risk of myelodysplastic syndromes and acute myeloid leukemia; however, the mechanisms underlying the pathophysiology of GATA2 deficiency remain still unclear. We developed two different mouse models that are based on serial and limiting donor cell transplantation of (aged) GATA2 haploinsufficient cells and mirror the symptoms of GATA2 deficiency. Similar to what has been observed in patients, our models show that GATA2 haploinsufficiency leads to B lymphopenia, monocytopenia, lethal bone marrow failure (BMF), myelodysplasia and leukemia. Leukemia arises exclusively as a result of BMF, driven by somatic aberrations and accompanied by increased Myc target expression and genomic instability. These findings were confirmed in human GATA2+/- K562 cell lines showing defects in cytokinesis and are in line with the fact that monosomy 7 and trisomy 8 are frequent events in patients with MDS. Key pointsO_LIIn a mouse model for GATA2 deficiency, leukemia emerges from bone marrow failure C_LIO_LIMaladaptation to proliferative signals and chromosomal segregation defects contribute to the hematological phenotypes in GATA2 deficiency C_LI

cell biology↗

bioRxiv2023

RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils

The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancies (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 regulates inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte-monocyte progenitors (GMPs) to restrict the inflammatory response of neutrophils to toll-like receptor 4 (TLR4) signaling. Loss of RUNX1 in GMPs increased the TLR4 coreceptor CD14 on neutrophils, which contributed to neutrophils increased inflammatory cytokine production in response to the TLR4 ligand lipopolysaccharide. RUNX1 loss increased the chromatin accessibility of retrotransposons in GMPs and neutrophils and induced a type I interferon signature characterized by enriched footprints for signal transducer and activator of transcription (STAT1::STAT2) and interferon regulatory factors (IRF) in opened chromatin, and increased expression of interferon-stimulated genes. The overproduction of inflammatory cytokines by neutrophils was reversed by inhibitors of type I IFN signaling. We conclude that RUNX1 restrains the chromatin accessibility of retrotransposons in GMPs and neutrophils, and that loss of RUNX1 increases proinflammatory cytokine production by elevating tonic type I interferon signaling.

developmental biology↗

bioRxiv2022

Gata2-regulated Gfi1b expression controls endothelial programming during endothelial-to-hematopoietic transition

The first hematopoietic stem cells (HSCs) are formed through endothelial-to-hematopoietic transition (EHT) events during embryonic development. The transcription factor GATA2 is a crucial regulator of EHT and HSC function throughout life. Because GATA2 haploinsufficiency patients have inborn mutations, prenatal defects are likely to have an influence on disease development. In mice, Gata2 haploinsufficiency (Gata2+/-) reduces the number and the functionality of embryonic hematopoietic stem and progenitor cells (HSPCs) generated through EHT. However, the embryonic HSPC pool is heterogeneous and the mechanisms underlying this defect in Gata2+/- embryos are unclear. Here, we investigated whether Gata2 haploinsufficiency selectively affects a cellular subset undergoing EHT. We show that Gata2+/- HSPCs initiate but cannot fully activate hematopoietic programming during EHT. In addition, due to reduced activity of the endothelial repressor Gfi1b, Gata2+/- HSPCs cannot repress the endothelial identity to complete maturation. Finally, we show that hematopoietic-specific induction of gfi1b can restore HSC production in gata2b-null (gata2b-/-) zebrafish embryos. This study illustrates pivotal roles of Gata2 on the regulation of transcriptional network governing HSPC identity throughout EHT. HighlightsO_LIMaturation of embryonic Gata2+/- HSPCs is disturbed due to aberrant endothelial gene expression and incomplete activation of hematopoietic transcriptional programming. C_LIO_LIGata2 activates Gfi1b to repress endothelial identity of embryonic HSPCs during maturation. C_LIO_LIHematopoietic-specific induction of gfi1b restores the number of embryonic HSCs in gata2b-/- zebrafish. C_LI

developmental biology↗

bioRxiv2021

Gata2b haploinsufficiency causes aberrant transcriptional signatures in HSPCs resulting in myeloid and erythroid dysplasia in zebrafish

The transcription factor GATA2 has pivotal roles in hematopoiesis. Germline GATA2 mutations in patients result in GATA2 haploinsufficiency syndrome characterized by immunodeficiency, bone marrow failure, and predispositions to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical symptoms in GATA2 patients are diverse and mechanisms driving GATA2 related phenotypes largely unknown. To explore the impact of GATA2 haploinsufficiency on hematopoiesis, we generated a zebrafish model carrying a heterozygous mutation of gata2b (gata2b+/-), an orthologue of GATA2. Morphological analysis revealed myeloid and erythroid dysplasia in gata2b+/- kidney marrow (KM). single nucleus (sn)-ATAC-seq showed that the co-accessibility between the transcription start site (TSS) and a +3.5-4.1kb enhancer was more robust in gata2b+/- zebrafish HSPCs compared to wild type, increasing gata2b expression. This is suggestive of an auto-regulatory feedback mechanism, where gata2b expression remains at sufficient levels after the loss of a single allele to maintain the HSPC pool. As a result, gata2b+/- chromatin is also more accessible in the erythroid and myeloid lineage, causing several defects. scRNA-seq data revealed a differentiation delay in erythroid progenitors, hallmarked by downregulation of intrinsic signals like cytoskeletal transcripts, aberrant proliferative signatures, and downregulation of Gata1a, a master regulator of erythropoiesis, likely preceding erythroid dysplasia. This shows that the cell intrinsic compensatory mechanisms for the maintenance of normal levels of Gata2b to maintain HSPC integrity result in aberrant lineage differentiation and a preleukemia syndrome.

cancer biology↗

bioRxiv2019

Single cell transcriptome analysis reveals an essential role for Gata2b in hematopoietic lineage decisions in zebrafish

Hematopoietic stem cells (HSCs) are tightly controlled to keep a balance between myeloid and lymphoid cell differentiation. Gata2 is a pivotal hematopoietic transcription factor required for HSC generation and maintenance. We generated a zebrafish mutant for the mammalian Gata2 orthologue, gata2b. We found that in adult zebrafish, gata2b is required for both neutrophilic- and monocytic lineage differentiation. Single cell transcriptome analysis revealed that the myeloid defect present in Gata2b deficient zebrafish arise in the most immature hematopoietic stem and progenitor cell (HSPC) compartment and that this population is instead committed towards the lymphoid and erythroid lineage. Taken together, we find that Gata2b is vital for the fate choice between the myeloid and lymphoid lineages.

immunology↗