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PHF6 suppresses self-renewal of leukemic stem cells in AML

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

PROVIDER: PRJNA1128120 | ENA |

REPOSITORIES: ENA

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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 suppresses self-renewal of leukemic stem cells in AML

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-06-25 | GSE270756 | GEO

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

Transcriptome changes caused by Phf6 deletion in Committed leukemic cells from the retroviral-HoxA9 AML mouse model [RNA-seq Committed leukemic cell]

Project description:Hematopoietic conditional knockout (cKO) of Phf6 in a mouse retroviral-HoxA9 AML model led to increased transplantability. We performed bulk RNA-Seq on the 'committed' population (c-Kit+, Ly6C+) sort purified from primary recipients of HoxA9-transduced Ctrl (Vav-Cre/+, Phf6 +/Y marrow transduced with HoxA9) and cKO cells (Vav-Cre/+, Phf6 flox/Y marrow transduced with HoxA9) 8 weeks after transplantation. Our results reveal that Phf6 deletion has minimal effects on the transcriptome of the committed population (see separately deposited series for effects on the transcriptome of leukemia initiating [LIC-e] cells).

2023-12-15 | GSE249109 | 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

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Disrupting mitochondrial copper distribution inhibits leukemic stem cell self-renewal

Project description:Disrupting mitochondrial copper distribution inhibits leukemic stem cell self-renewal

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

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

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A STAT5B-CD9 axis determines self-renewal in hematopoietic and leukemic stem cells

Project description:The transcription factors STAT5A and STAT5B are critical in hematopoiesis and leukemia. They are widely believed to have redundant functions but we describe a unique role for STAT5B in driving the self-renewal of hematopoietic and leukemic stem cells (HSCs/LSCs). We find STAT5B to be specifically activated in HSCs and LSCs, where it induces many genes associated with quiescence and self-renewal, including the surface marker CD9. Levels of CD9 represent a prognostic marker for patients with STAT5-driven leukemia and our findings suggest that anti-CD9 antibodies may be useful in their treatment to target and eliminate LSCs. We show that it is vital to consider STAT5A and STAT5B as distinct entities in normal and malignant hematopoiesis.

2021-12-31 | GSE178648 | GEO

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

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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

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