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ROBO1 deficiency impairs hematopoietic stem progenitor cell self-renewal and erythropoiesis via CDC42 and predicts poor prognosis in MDS

ABSTRACT: ROBO1 deficiency impairs hematopoietic stem progenitor cell self-renewal and erythropoiesis via CDC42 and predicts poor prognosis in MDS

PROVIDER: PRJNA967222 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24425900_1.fastq.gz	Fastqsanger.gz
	SRR24425900_2.fastq.gz	Fastqsanger.gz
	SRR24425901_1.fastq.gz	Fastqsanger.gz
	SRR24425901_2.fastq.gz	Fastqsanger.gz
	SRR24425896_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

ROBO1 deficiency impairs hematopoietic stem progenitor cell self-renewal and erythropoiesis via CDC42 and predicts poor prognosis in MDS

Project description:We previously identified inactivating mutations in roundabout guidance receptor 1 (ROBO1) in patients with myelodysplastic syndrome (MDS), which was associated with poor prognosis and susceptibility to acute myeloid leukemia (AML) transformation. Nonetheless, the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here we report that the ablation of Robo1 in mice is sufficient to confer MDS-like disease with anemia and multilineage dysplasia. More specifically, Robo1 deficiency impairs the self-renewal and differentiation capacity of hematopoietic stem progenitor cells (HSPCs) and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors (MEPs), which causes a blockage in the early stages of erythropoiesis in mice. Similarly, Robo1-deficienct HSPCs recapitulated MDS-like disease with anemia and multilineage dysplasia in transplanted mice. Correspondingly, clinical data also reveal that low expression of ROBO1 is associated with shortened survival, severe anemia and a high risk of AML transformation in patients with MDS. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-GTPase family, serves as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the proliferation of erythroid colonies in Robo1 deficient mice. In contrast, Cdc42 inhibitor (CASIN) effectively attenuates the erythroid colony formation of HSPCs. Collectively, our results suggest that Robo1 deficiency may provide a promising therapeutic target against MDS by impairing HSPC self-renewal and erythropoiesis via CDC42, predicting a poor prognosis for severe anemia and a high risk of AML transformation in MDS.

2023-12-01 | GSE231641 | GEO

Affymetrix SNP array data for myelodysplastic syndromes (MDS) samples

Project description:The progressive mechanism of myelodysplastic syndrome (MDS) remains unknown. We report that ROBO1 and ROBO2 are identified as novel progression-related somatic mutations using whole-exome and targeted sequencing in six of 16 (37.5%) paired MDS patients undergoing disease progression. To investigated the effect of ROBO1 or ROBO2 on ROBO1/2 CN number and LOH, we employed a Cytosan 750K chip to analyze the copy-number variations (CNVs) and loss of heterogeneity (LOH) in MDS patients with ROBO1&2 mutations. Copy number and LOH analysis of Affymetrix CytoScan 750K array was performed for 14 MDS patients with ROBO1 or ROBO2 mutations

2015-09-15 | E-GEOD-73005 | biostudies-arrayexpress

Affymetrix SNP array data for myelodysplastic syndromes (MDS) samples

2015-09-15 | GSE73005 | GEO

RNA-seq of nulliparus Robo1+/+ and Robo1-/- luminal progenitors

Project description:The goal of the study was to compare gene expression of Robo1+/+ and Robo1-/- luminal progenitors. Total RNAs were then extracted from FACS purified luminal progenitor cells, harvested from Robo1+/+ or Robo1-/- mice (n=3 per genotype, two animals per n) using TRIreagent LS (Sigma, T3934). Poly(A)+ RNA sequencing libraries were made from each sample using the TruSeq RNA library preparation kit v.1 (Illumina). Illumina RNA PolyA library preparation guide. A total of 6 libraries were created by PCR amplification with Illumina barcoding primers using kit recommended conditions and quantified using a Bioanalyzer DNA 1000 kit (Agilent).

2021-10-12 | GSE164707 | GEO

RNA-seq of nulliparus Robo1+/+ and Robo1-/- luminal progenitors

Project description:RNA-seq of nulliparus Robo1+/+ and Robo1-/- luminal progenitors

| PRJNA691604 | ENA

SF3B1 deficiency impairs human erythropoiesis via activation of p53 pathway: implications for understanding of ineffective erythropoiesis in MDS

Project description:SF3B1 deficiency impairs human erythropoiesis via activation of p53 pathway: implications for understanding of ineffective erythropoiesis in MDS

| PRJNA724732 | ENA

Transcriptomic profiling of 4T1 cells depleted for Id1/3 and Robo1

Project description:Id1 and its closely related family member Id3 are expressed by a diversity of stem and progenitor cells. We show that Id1/3 are required for the self-renewal and proliferation of triple negative breast cancer (TNBC) cells both in vitro and in vivo. Furthermore, we identified that Id1/3 negatively regulates the tumour suppressor gene Robo1. Depletion of Robo1 could rescue the proliferative defect induced by Id1/3 knockdown. To understand the mechanisms by which Robo1 rescues cell proliferation in Id1/3 depleted cells, we performed RNA-Sequencing on 4T1 cells with Dox-inducible Id1/3 KD and/or Robo1 depletion using siRNA. We conclude that following Id1/3 knockdown, Robo1 is induced and exerts anti-proliferative effects via suppression of a Myc transcriptional program.

2020-10-31 | GSE129858 | GEO

Functional role of SLIT2 and ROBO1 in trophoblasts

Project description:Analysis of the effect of SLIT2 and ROBO1 siRNA experiment

2019-05-27 | GSE119101 | GEO

CDC42 inhibitors regulate genes involved in skin vasculaization

Project description:RhoJ protein has 55% homology with CDC42 and is highly expressed in endothelial cells. Both proteins regulate migration and contraction in endothelial cells through the activation of typrosine kinase receptors that control angiogenesis. To better understand how CDC42 inhibitors modulate angiogenesis, we performed bulk RNA sequening on wildtype skin treated with 12 mg/kg ARN22089 or vehicle twice a day for a week. Expression profiling showed that CDC42 inhibitors modulate skin vascularization. Some of the genes downregulated after CDC42 inhibitor treatment in wildtype skin involves CDC42 signaling and cell adhesion and putative angiogenesis regulators including CD177, CCL12, and CD34. Endothelial markers such as Lyve1 and Cd34 were also downregulated.

2025-06-16 | GSE298488 | GEO

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

Project description:Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 knockout screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Genetic perturbation or small molecule inhibition of PTP4A2 activity represses axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1), exploiting a functional dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies mimic effects of PTP4A2 inhibition. Since a pan-PTP4A inhibitor was limited by poor penetrance across the blood brain barrier (BBB) in vivo, a second-generation chimeric antigen receptor (CAR)-T cell therapy was engineered against ROBO1 that elicits specific and potent anti-tumor responses in vivo. A single dose of anti-ROBO1 CAR-T cells doubles median survival in patient-derived xenograft (PDX) models of recurrent glioblastoma, and also eradicates tumors in ~50% of mice in PDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A-ROBO1 signaling axis at GBM recurrence, with potential in other malignant brain tumors.

2024-08-30 | GSE240490 | GEO

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