RNA sequencing of isogenic Phf6 wild type and Phf6 knockout mouse T-ALL cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE117165 | GEO | 2019/07/31
REPOSITORIES: GEO
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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
Project description:Analysis of the mutational landscape of various hematological malignancies has shown that key regulators implicated in lineage commitment and differentiation are frequently implicated in leukemic transformation. In T-cell acute lymphoblastic leukemia, the role of various oncogenic and tumor suppressing transcription factors has been investigated. More recently, an exceptional high prevalence of mutations affecting epigenetic modifiers in T-ALL has also been noted. In order to understand the exact contribution of such lesions to normal differentiation and oncogenic transformation, further functional characterization of this subclass of proteins is warranted. PHF6 is one of these key epigenetic players, which was described as a frequently mutated and deleted novel tumor suppressor in T-ALL. In a first step towards unraveling the role of PHF6 in normal and malignant hematopoiesis, we characterized the function of PHF6 in both normal T-cell differentiation and other hematopoietic lineages as a prelude to understand its contribution to leukemogenesis. Here, we show for the first time that PHF6 controlled epigenetic regulation positively controls a NOTCH1 gene signature and the effects observed on T-lineage differentiation seem to be additive with Notch1. In this study, we show for the first time that PHF6 is a master regulator of early hematopoietic differentiation along the T-cell, B-cell, myeloid and NK-cell lineages.
2020-12-01 | GSE85372 | GEO
Project description:Analysis of the mutational landscape of various hematological malignancies has shown that key regulators implicated in lineage commitment and differentiation are frequently implicated in leukemic transformation. In T-cell acute lymphoblastic leukemia, the role of various oncogenic and tumor suppressing transcription factors has been investigated. More recently, an exceptional high prevalence of mutations affecting epigenetic modifiers in T-ALL has also been noted. In order to understand the exact contribution of such lesions to normal differentiation and oncogenic transformation, further functional characterization of this subclass of proteins is warranted. PHF6 is one of these key epigenetic players, which was described as a frequently mutated and deleted novel tumor suppressor in T-ALL. In a first step towards unraveling the role of PHF6 in normal and malignant hematopoiesis, we characterized the function of PHF6 in both normal T-cell differentiation and other hematopoietic lineages as a prelude to understand its contribution to leukemogenesis. Here, we show for the first time that PHF6 controlled epigenetic regulation positively controls a NOTCH1 gene signature and the effects observed on T-lineage differentiation seem to be additive with Notch1. In this study, we show for the first time that PHF6 is a master regulator of early hematopoietic differentiation along the T-cell, B-cell, myeloid and NK-cell lineages.
2020-12-01 | GSE85371 | GEO
Project description:Analysis of the mutational landscape of various hematological malignancies has shown that key regulators implicated in lineage commitment and differentiation are frequently implicated in leukemic transformation. In T-cell acute lymphoblastic leukemia, the role of various oncogenic and tumor suppressing transcription factors has been investigated. More recently, an exceptional high prevalence of mutations affecting epigenetic modifiers in T-ALL has also been noted. In order to understand the exact contribution of such lesions to normal differentiation and oncogenic transformation, further functional characterization of this subclass of proteins is warranted. PHF6 is one of these key epigenetic players, which was described as a frequently mutated and deleted novel tumor suppressor in T-ALL. In a first step towards unraveling the role of PHF6 in normal and malignant hematopoiesis, we characterized the function of PHF6 in both normal T-cell differentiation and other hematopoietic lineages as a prelude to understand its contribution to leukemogenesis. Here, we show for the first time that PHF6 controlled epigenetic regulation positively controls a NOTCH1 gene signature and the effects observed on T-lineage differentiation seem to be additive with Notch1. In this study, we show for the first time that PHF6 is a master regulator of early hematopoietic differentiation along the T-cell, B-cell, myeloid and NK-cell lineages.
2020-12-01 | GSE85369 | GEO
Project description:Analysis of the mutational landscape of various hematological malignancies has shown that key regulators implicated in lineage commitment and differentiation are frequently implicated in leukemic transformation. In T-cell acute lymphoblastic leukemia, the role of various oncogenic and tumor suppressing transcription factors has been investigated. More recently, an exceptional high prevalence of mutations affecting epigenetic modifiers in T-ALL has also been noted. In order to understand the exact contribution of such lesions to normal differentiation and oncogenic transformation, further functional characterization of this subclass of proteins is warranted. PHF6 is one of these key epigenetic players, which was described as a frequently mutated and deleted novel tumor suppressor in T-ALL. In a first step towards unraveling the role of PHF6 in normal and malignant hematopoiesis, we characterized the function of PHF6 in both normal T-cell differentiation and other hematopoietic lineages as a prelude to understand its contribution to leukemogenesis. Here, we show for the first time that PHF6 controlled epigenetic regulation positively controls a NOTCH1 gene signature and the effects observed on T-lineage differentiation seem to be additive with Notch1. In this study, we show for the first time that PHF6 is a master regulator of early hematopoietic differentiation along the T-cell, B-cell, myeloid and NK-cell lineages.
2020-12-01 | GSE85370 | GEO
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
Project description:RNA sequencing of isogenic Phf6 wild type and Phf6 knockout mouse T-ALL cells
| PRJNA481336 | ENA
Project description:Inactivating mutations in the zinc finger gene PHF6 are seen in approximately 40% of adult T-cell acute lymphoblastic leukemias (T-ALLs) and 3% of adult acute myeloid leukemias (AMLs). The absence of PHF6 mutations in B-cell lineage malignancies has led to the hypothesis that PHF6 may act as a lineage-specific tumor suppressor gene. Here, we demonstrate that PHF6 plays a critical role in regulating B-cell identity in the context of B-cell precursor acute lymphoblastic leukemia (preB-ALL). Transplantation of Phf6 knockout preB-ALL cells (hereafter referred to as Phf6KO cells) into immunocompetent syngeneic recipients resulted in the development of a fully penetrant lymphoma-like disease. Strikingly, the resulting lymphomas showed robust up-regulation of the canonical T-cell marker CD4, suggesting that Phf6KO cells adopt a T-cell program in the context of leukemogenesis. RNA sequencing analysis revealed numerous differentially expressed (DE) genes in Phf6WT and Phf6KO cells, including a significant down-regulation of genes and gene sets involved in pathways important for B-cell development. Chromatin immunoprecipitation followed by high-throughput sequencing analysis revealed that PHF6 co-localizes with H3K27ac signals close to the transcription start sites (TSSs) and enhancer regions of a significant proportion of DE genes. Notably, regions flanking the TSS of DE genes showed significant enrichment for binding sites of several well-described master regulators of B-cell development, including PU.1, EGR-1, EBF-1, NF-kB, TCF3 and TCF12. We found that PHF6 and TCF12 physically interact in preB-ALL cells, suggesting that these factors act synergistically in the establishment and maintenance of B-cell identity. In addition, we found that a human PHF6 mutant T-ALL cell line has an incompletely rearranged IGH locus, strongly suggesting that T-ALL can have a B-cell origin. These findings reveal an essential role for PHF6 in the establishment and maintenance of B-cell identity in preB-ALL by directly activating genes that are crucial for B-cell lineage commitment and maintenance. Collectively, these results indicate that loss of function of PHF6 in preB-ALL leads to an unstable cellular state in which cells acquire alternate developmental programs (such as the T-lineage program) to survive, potentially explaining the apparent absence of PHF6 mutations in human B cell-lineage malignancies.
2017-07-10 | GSE74878 | GEO
Project description:Inactivating mutations in the zinc finger gene PHF6 are seen in approximately 40% of adult T-cell acute lymphoblastic leukemias (T-ALLs) and 3% of adult acute myeloid leukemias (AMLs). The absence of PHF6 mutations in B-cell lineage malignancies has led to the hypothesis that PHF6 may act as a lineage-specific tumor suppressor gene. Here, we demonstrate that PHF6 plays a critical role in regulating B-cell identity in the context of B-cell precursor acute lymphoblastic leukemia (preB-ALL). Transplantation of Phf6 knockout preB-ALL cells (hereafter referred to as Phf6KO cells) into immunocompetent syngeneic recipients resulted in the development of a fully penetrant lymphoma-like disease. Strikingly, the resulting lymphomas showed robust up-regulation of the canonical T-cell marker CD4, suggesting that Phf6KO cells adopt a T-cell program in the context of leukemogenesis. RNA sequencing analysis revealed numerous differentially expressed (DE) genes in Phf6WT and Phf6KO cells, including a significant down-regulation of genes and gene sets involved in pathways important for B-cell development. Chromatin immunoprecipitation followed by high-throughput sequencing analysis revealed that PHF6 co-localizes with H3K27ac signals close to the transcription start sites (TSSs) and enhancer regions of a significant proportion of DE genes. Notably, regions flanking the TSS of DE genes showed significant enrichment for binding sites of several well-described master regulators of B-cell development, including PU.1, EGR-1, EBF-1, NF-kB, TCF3 and TCF12. We found that PHF6 and TCF12 physically interact in preB-ALL cells, suggesting that these factors act synergistically in the establishment and maintenance of B-cell identity. In addition, we found that a human PHF6 mutant T-ALL cell line has an incompletely rearranged IGH locus, strongly suggesting that T-ALL can have a B-cell origin. These findings reveal an essential role for PHF6 in the establishment and maintenance of B-cell identity in preB-ALL by directly activating genes that are crucial for B-cell lineage commitment and maintenance. Collectively, these results indicate that loss of function of PHF6 in preB-ALL leads to an unstable cellular state in which cells acquire alternate developmental programs (such as the T-lineage program) to survive, potentially explaining the apparent absence of PHF6 mutations in human B cell-lineage malignancies.
2017-07-31 | GSE98716 | GEO
Project description:Inactivating mutations in the zinc finger gene PHF6 are seen in approximately 40% of adult T-cell acute lymphoblastic leukemias (T-ALLs) and 3% of adult acute myeloid leukemias (AMLs). The absence of PHF6 mutations in B-cell lineage malignancies has led to the hypothesis that PHF6 may act as a lineage-specific tumor suppressor gene. Here, we demonstrate that PHF6 plays a critical role in regulating B-cell identity in the context of B-cell precursor acute lymphoblastic leukemia (preB-ALL). Transplantation of Phf6 knockout preB-ALL cells (hereafter referred to as Phf6KO cells) into immunocompetent syngeneic recipients resulted in the development of a fully penetrant lymphoma-like disease. Strikingly, the resulting lymphomas showed robust up-regulation of the canonical T-cell marker CD4, suggesting that Phf6KO cells adopt a T-cell program in the context of leukemogenesis. RNA sequencing analysis revealed numerous differentially expressed (DE) genes in Phf6WT and Phf6KO cells, including a significant down-regulation of genes and gene sets involved in pathways important for B-cell development. Chromatin immunoprecipitation followed by high-throughput sequencing analysis revealed that PHF6 co-localizes with H3K27ac signals close to the transcription start sites (TSSs) and enhancer regions of a significant proportion of DE genes. Notably, regions flanking the TSS of DE genes showed significant enrichment for binding sites of several well-described master regulators of B-cell development, including PU.1, EGR-1, EBF-1, NF-kB, TCF3 and TCF12. We found that PHF6 and TCF12 physically interact in preB-ALL cells, suggesting that these factors act synergistically in the establishment and maintenance of B-cell identity. In addition, we found that a human PHF6 mutant T-ALL cell line has an incompletely rearranged IGH locus, strongly suggesting that T-ALL can have a B-cell origin. These findings reveal an essential role for PHF6 in the establishment and maintenance of B-cell identity in preB-ALL by directly activating genes that are crucial for B-cell lineage commitment and maintenance. Collectively, these results indicate that loss of function of PHF6 in preB-ALL leads to an unstable cellular state in which cells acquire alternate developmental programs (such as the T-lineage program) to survive, potentially explaining the apparent absence of PHF6 mutations in human B cell-lineage malignancies.
2017-07-10 | GSE77456 | GEO