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Transcriptomic changes in THP1 human AML cell line on PHF6 knockout, PHF6R274Q mutation, PHIP knockout, and double knockout of PHF6 and PHIP compared to wildtype cells

ABSTRACT: PHF6 is a transcriptional regulator mutated in 3-5% of acute myeloid leukemia. To understand the effect of loss and clinical mutation of PHF6 on the transcriptome of myeloid cells, we generated multiple wildtype and PHF6 knockout clones, as well as clones expressing the most common clinical mutant of the protein-PHF6R274Q. We observed that both single and double knockouts and mutation of PHF6 shifted the cells towards stemness and away from differentiation. Additionally we identified PHIP as a possible functional partner for PHF6. To investigate their common biological function, we generated multiple single knockout clones of PHIP as well as double knockout clones of PHIP and PHF6, and observed that, similar to single knockout of PHF6, PHIP knockout and double knockout also shifted cells towards stemness and away from differentiation. Collectively, our experiments show that PHF6 and PHIP, separately identified as being mutated in AML, exert similar downstream effects on the AML transcriptome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281475 | GEO | 2024/11/15

REPOSITORIES: GEO

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Transcriptomic changes in PHF6 knockout THP1 human AML cell line on rescue with PHF6 wildtype (with and without PHIP) or rescue with PHF6R274Q mutant

Project description:PHF6 is a transcriptional regulator mutated in 3-5% of acute myeloid leukemia. To understand the effect of loss and clinical mutation of PHF6 on the transcriptome of myeloid cells, we generated multiple wildtype and PHF6 knockout clones, as well as clones expressing the most common clinical mutant of the protein-PHF6R274Q. We observed that both single and double knockouts and mutation of PHF6 shifted the cells towards stemness and away from differentiation. Additionally we identified PHIP as a possible functional partner for PHF6. To investigate their common biological function, we generated multiple single knockout clones of PHIP as well as double knockout clones of PHIP and PHF6, and observed that, similar to single knockout of PHF6, PHIP knockout and double knockout also shifted cells towards stemness and away from differentiation. Collectively, our experiments show that PHF6 and PHIP, separately identified as being mutated in AML, exert similar downstream effects on the AML transcriptome.

2024-11-15 | GSE281624 | GEO

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Project description:PHF6 is a transcriptional regulator mutated in 3-5% of acute myeloid leukemia. To understand how PHF6 and its functional partner PHIP interact with each other on chromatin, we performed ChIP-Seq for PHF6 (in the presence and absence of PHIP), and for PHIP. We observd that PHF6 and PHIP peaks overlap on chromatin, and PHF6 requires PHIP for its chromatin occupancy. ATAC-Seq and H3K27ac ChIP-Seq showed that PHF6 and PHIP occupy open and active regions of the genome.

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

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

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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

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