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Phf6-null hematopoietic stem cells have enhanced self-renewal capacity and oncogenic potentials

ABSTRACT: Phf6-null hematopoietic stem cells have enhanced self-renewal capacity and oncogenic potentials

PROVIDER: PRJNA531434 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8866540.fastq.gz	Fastqsanger.gz
	SRR8866550.fastq.gz	Fastqsanger.gz
	SRR8866560.fastq.gz	Fastqsanger.gz
	SRR8866541.fastq.gz	Fastqsanger.gz
	SRR8866551.fastq.gz	Fastqsanger.gz

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Similar Datasets

Phf6-null hematopoietic stem cells have enhanced self-renewal capacity and oncogenic potentials

Project description:Plant homeodomain finger gene 6 (PHF6) encodes a 365-amino-acid protein containing two plant homology domain fingers. Germline mutations of human PHF6 cause Börjeson–Forssman–Lehmann syndrome, a congenital neurodevelopmental disorder. Loss-of-function mutations of PHF6 are detected in patients with acute leukemia, mainly of T cell lineage and in a small proportion of myeloid lineage. The functions of PHF6 in physiological hematopoiesis and leukemogenesis remain incompletely defined. To address this question, we generated a conditional Phf6 knockout mouse model and investigated the impact of Phf6 loss on the hematopoietic system. We found that Phf6 knockout mice at 8-week age had reduced numbers of CD4+ and CD8+ T cells in the peripheral blood compared to the wild-type littermates. There were decreased granulocyte-monocytic progenitors but increased Lin-c-Kit+Sca-1+ (LSK) cells in the marrow of young Phf6 knockout mice. Functional studies including competitive repopulation unit and serial transplantation assays revealed an enhanced reconstitution and self-renewal capacity in Phf6 knockout hematopoietic stem cells (HSCs). Aged Phf6 knockout mice had myelodysplasia-like presentations including decreased platelet counts, megakaryocyte dysplasia, and enlarged spleen related to extramedullary hematopoiesis. Moreover, we found that Phf6 loss lowered the threshold of NOTCH1-induced leukemic transformation at least partially through increased leukemia-initiating cells. Transcriptome analysis on the restrictive rare HSC subpopulations revealed upregulated cell cycling and oncogenic functions, with alteration of expression of key genes in those pathways. In summary, our studies demonstrate the in vivo crucial roles of Phf6 in physiological and malignant hematopoiesis.

2019-08-21 | GSE129465 | GEO

Phf6-null hematopoietic stem cells have enhanced self-renewal capacity and oncogenic potentials.

Project description:Plant homeodomain finger gene 6 (PHF6) encodes a 365-amino-acid protein containing 2 plant homology domain fingers. Germline mutations of human PHF6 cause Börjeson-Forssman-Lehmann syndrome, a congenital neurodevelopmental disorder. Loss-of-function mutations of PHF6 are detected in patients with acute leukemia, mainly of T-cell lineage and in a small proportion of myeloid lineage. The functions of PHF6 in physiological hematopoiesis and leukemogenesis remain incompletely defined. To address this question, we generated a conditional Phf6 knockout mouse model and investigated the impact of Phf6 loss on the hematopoietic system. We found that Phf6 knockout mice at 8 weeks of age had reduced numbers of CD4+ and CD8+ T cells in the peripheral blood compared with the wild-type littermates. There were decreased granulocyte-monocytic progenitors but increased Lin-c-Kit+Sca-1+ cells in the marrow of young Phf6 knockout mice. Functional studies, including competitive repopulation unit and serial transplantation assays, revealed an enhanced reconstitution and self-renewal capacity in Phf6 knockout hematopoietic stem cells (HSCs). Aged Phf6 knockout mice had myelodysplasia-like presentations, including decreased platelet counts, megakaryocyte dysplasia, and enlarged spleen related to extramedullary hematopoiesis. Moreover, we found that Phf6 loss lowered the threshold of NOTCH1-induced leukemic transformation at least partially through increased leukemia-initiating cells. Transcriptome analysis on the restrictive rare HSC subpopulations revealed upregulated cell cycling and oncogenic functions, with alteration of key gene expression in those pathways. In summary, our studies show the in vivo crucial roles of Phf6 in physiological and malignant hematopoiesis.

| S-EPMC6693005 | biostudies-literature

R274X mutation in Phf6 enhances self-renewal and repopulation capacity of hematopoietic stem cells

Project description:R274X mutation in Phf6 enhances self-renewal and repopulation capacity of hematopoietic stem cells

| PRJNA831853 | ENA

PHF6 suppresses self-renewal of leukemic stem cells in AML

Project description:PHF6 suppresses self-renewal of leukemic stem cells in AML

| PRJNA1128120 | ENA

Transcriptome changes caused by PHF6 knockout in THP1 human AML cell line

Project description:CRISPR Cas9 guided knockout (KO) of PHF6 in human THP1 AML cell line. We performed bulk RNA-Seq on knockout (PHF6 KO) and wildtype (CTRL) clones derived from THP1 cells transduced with lentiviral vectors encoding Cas9 protein and either PHF6 gRNAs or non-targeting gRNAs. Our results reveal that PHF6 knockout upregulates self-renewal gene sets and downregulates myeloid differentiation gene sets.

2024-09-18 | GSE277149 | GEO

Genome-wide chromatin accessibility profiling of LT-HSCs isolated from WT and Phf6-deficient mice

Project description:The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL.

2021-06-23 | GSE178739 | GEO

Loss of Phf6 enhances HSC self-renewal and leukemia stem cell activity

Project description:Loss of Phf6 enhances HSC self-renewal and leukemia stem cell activity

| PRJNA740257 | ENA

RNA sequencing of isogenic Phf6 wild type and Phf6 knockout mouse T-ALL cells

Project description:Loss-of-function mutations Phf6 occur frequently in both adult and pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL). Although Phf6 is widely expressed, little is known about its proposed function as epigenetic regulator and tumor suppressor. To address the role of Phf6 in the leukemia development, here we analyze by RNAseq the gene expression profiles of isogenic Phf6 wild type and Phf6 knockout leukemia cells transformed by overexpression of an oncogenic mutant form of the NOTCH1 receptor.

2019-07-31 | GSE117165 | GEO

PHF6 OCCUPANCYIN HUMAN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Project description:Here we identify the genome-wide occupancy of PHF6 in T-ALL cells. Human T-ALL cells were cross-linked with formaldehyde for 20 min. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract (WCE) was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total PHF6 (Bethyl A301-451A). This represents the ChIP-seq portion of this dataset.

2014-04-01 | E-GEOD-45864 | biostudies-arrayexpress

Transcriptional reprogramming of neural stem cells by a PHF6/EphR signalling pathway [RNA-seq]

Project description:The plant homeodomain zinc finger protein,PHF6, is a transcriptional regulator, with its germline mutations causing the X-linked intellectual disability (XLID), Börjeson-Forssman-Lehmann syndrome (BFLS).The precise mechanisms by whichPHF6regulates transcription and how its mutant forms lead to XLID remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex, most of which overlap (CA)n-microsatellite repeats near genes involved in central nervous system development and neurogenesis. Mice harbouring BFLS patient mutations exhibit defects in neurogenesis and altered neural stem cell fate. Mechanistically, we find that PHF6 regulatesa panel of Ephrin receptors (EphRs)and that PHF6regulation ofEphRis impaired in BFLS mice and ina conditionalPhf6knock-out mouse model. We report that mice harboring BFLS mutations exhibit an increase in embryonic neural stem cell (eNSC) self-renewal, a significant attenuation of newly born neurons, and thatEphRknockdown phenocopies the PHF6 loss-of-function defects in altering eNSC fate. Our results suggest that alterations in eNSC fate specification via a PHF6/EphRtranscriptional pathway leads to impaired neurogenesis in BFLS

2024-02-07 | GSE247837 | GEO

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