Similar Datasets
Project description:Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for patients. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML in adults by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the epigenetic mechanism underpinning the enhanced self-renewal conferred by cohesin-haploinsufficiency. First, given the substantial difference in the mutational spectrum between pediatric and adult AML patients, we first sought to identify if HOXA9 was also elevated in children. Next, using primary HSPCs as a model we demonstrate that abnormal self-renewal due to cohesin loss is blocked by DOT1L inhibition. In cohesin-depleted cells, DOT1L inhibition is associated with H3K79me2 depletion and a concomitant increase in H3K27me3. Importantly, we find that there are cohesin-dependent gene expression changes that promote a leukemic profile, including HoxA overexpression, that are preferentially reversed by DOT1L inhibition. Our data further characterize how cohesin mutations contribute to AML development, identifying DOT1L as a potential therapeutic target for adult and pediatric AML patients harboring cohesin mutations.
| S-EPMC8012605 | biostudies-literature
Project description:Acute myelogenous leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the mechanism underpinning the enhanced self-renewal conferred by cohesin haploinsufficiency. Using primary (HSPCs) as a model we demonstrate that a reduction in a core cohesin subunit is associated with decreased H3K27me3 and increased H3K79me2, along with increased self-renewal capacity and a leukemic transcriptional profile. Inhibition of DOT1L in cohesin-depleted HSPCs restored normal self-renewal, H3K27me3 and H3K79me2 levels, and gene expression, identifying DOT1L as a potential therapeutic target in cohesin haploinsufficient AML. Together our data further characterizes the mechanism by which cohesin mutations contribute to AML and identifies DOT1L as a potential therapeutic target for AML patients harboring cohesin mutations.
2021-02-25 | GSE140360 | GEO
Project description:Acute myelogenous leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the mechanism underpinning the enhanced self-renewal conferred by cohesin haploinsufficiency. Using primary (HSPCs) as a model we demonstrate that a reduction in a core cohesin subunit is associated with decreased H3K27me3 and increased H3K79me2, along with increased self-renewal capacity and a leukemic transcriptional profile. Inhibition of DOT1L in cohesin-depleted HSPCs restored normal self-renewal, H3K27me3 and H3K79me2 levels, and gene expression, identifying DOT1L as a potential therapeutic target in cohesin haploinsufficient AML. Together our data further characterizes the mechanism by which cohesin mutations contribute to AML and identifies DOT1L as a potential therapeutic target for AML patients harboring cohesin mutations.
2021-02-25 | GSE140359 | GEO
Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss
| PRJNA589333 | ENA
Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [RNA-seq]
| PRJNA589334 | ENA
Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [ChIP-seq]
| PRJNA589335 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-09-24 | E-GEOD-60131 | biostudies-arrayexpress
Project description:The differentiation of patient-derived induced pluripotent stem cells (iPSCs) to committed fates such as neurons, muscle and liver is a powerful approach for understanding key parameters of human development and disease. Whether undifferentiated iPSCs themselves can be used to probe disease mechanisms is uncertain. Dyskeratosis congenita is characterized by defective maintenance of blood, pulmonary tissue and epidermal tissues and is caused by mutations in genes controlling telomere homeostasis. Short telomeres, a hallmark of dyskeratosis congenita, impair tissue stem cell function in mouse models, indicating that a tissue stem cell defect may underlie the pathophysiology of dyskeratosis congenita. Here we show that even in the undifferentiated state, iPSCs from dyskeratosis congenita patients harbour the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, because telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. These findings in iPSCs from dyskeratosis congenita patients reveal that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell-culture-based system for the development of targeted therapeutics.
| S-EPMC3155806 | biostudies-literature
Project description:Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.
| S-EPMC6195188 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2014-09-24 | GSE60131 | GEO