scholarly journals Mutant p53 Drives Clonal Hematopoiesis through Modulating Epigenetic Pathway

2019 ◽  
Author(s):  
Sisi Chen ◽  
Qiang Wang ◽  
Hao Yu ◽  
Maegan L. Capitano ◽  
Sasidhar Vemula ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Epigenetic Mechanism ◽  
Mutant P53 ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Induced Stress ◽  
Epigenetic Regulator ◽  
Radiation Induced

AbstractClonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. We discovered that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Further, genetic and pharmacological inhibition of EZH2 decrease the repopulating potential of p53 mutant HSPCs. Thus, we have uncovered an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

scholarly journals Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sisi Chen ◽  
Qiang Wang ◽  
Hao Yu ◽  
Maegan L. Capitano ◽  
Sasidhar Vemula ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Epigenetic Mechanism ◽  
Mutant P53 ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Induced Stress ◽  
Epigenetic Regulator ◽  
Radiation Induced

AbstractClonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

scholarly journals Gene Transcription as a Therapeutic Target in Leukemia

2021 ◽  
Vol 22 (14) ◽  
pp. 7340
Author(s):  
Alvina I. Khamidullina ◽  
Ekaterina A. Varlamova ◽  
Nour Alhuda Hammoud ◽  
Margarita A. Yastrebova ◽  
Alexandra V. Bruter
Keyword(s):  
Gene Transcription ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Mechanisms Of Action ◽  
Special Program ◽  
Cell Plasticity ◽  
Hematopoietic Stem ◽  
Promising Strategy ◽  
Tumor Cell Plasticity ◽  
Transcriptional Landscape

Blood malignancies often arise from undifferentiated hematopoietic stem cells or partially differentiated stem-like cells. A tight balance of multipotency and differentiation, cell division, and quiescence underlying normal hematopoiesis requires a special program governed by the transcriptional machinery. Acquisition of drug resistance by tumor cells also involves reprogramming of their transcriptional landscape. Limiting tumor cell plasticity by disabling reprogramming of the gene transcription is a promising strategy for improvement of treatment outcomes. Herein, we review the molecular mechanisms of action of transcription-targeted drugs in hematological malignancies (largely in leukemia) with particular respect to the results of clinical trials.

scholarly journals Discovering the drivers of clonal hematopoiesis

2020 ◽  
Author(s):  
Oriol Pich ◽  
Iker Reyes-Salazar ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Positive Selection ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Cancer Genomics ◽  
Variant Calling ◽  
Selective Advantage ◽  
Cancer Genes ◽  
Driver Genes ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis

AbstractMutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certain conditions drive clonal hematopoiesis (CH). While some CH drivers have been identified experimentally or through epidemiological studies, the compendium of all genes able to drive CH upon mutations in HSCs is far from complete. We propose that identifying signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, similarly as done to identify cancer genes. Using a reverse somatic variant calling approach, we repurposed whole-genome and whole-exome blood/tumor paired samples of more than 12,000 donors from two large cancer genomics cohorts to identify blood somatic mutations. The application of IntOGen, a robust driver discovery pipeline, to blood somatic mutations across both cohorts, and more than 24,000 targeted sequenced samples yielded a list of close to 70 genes with signals of positive selection in CH, available at http://www.intogen.org/ch. This approach recovers all known CH genes, and discovers novel candidates. Generating this compendium is an essential step to understand the molecular mechanisms of CH and to accurately detect individuals with CH to ascertain their risk to develop related diseases.

scholarly journals Persistent Epigenetic Reprogramming of Sweet Taste by Diet

2020 ◽  
Author(s):  
Anoumid Vaziri ◽  
Morteza Khabiri ◽  
Brendan T. Genaw ◽  
Christina E. May ◽  
Peter L. Freddolino ◽  
...  
Keyword(s):  
Neural Plasticity ◽  
Molecular Mechanisms ◽  
Control Diet ◽  
Sweet Taste ◽  
Taste Perception ◽  
Epigenetic Mechanism ◽  
High Sugar ◽  
Epigenetic Regulator ◽  
Transcriptional Changes ◽  
Gustatory Neurons

AbstractDiets rich in sugar, salt, and fat alter taste perception and food intake, leading to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of D. melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Importantly, half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.

scholarly journals Persistent epigenetic reprogramming of sweet taste by diet

2020 ◽  
Vol 6 (46) ◽  
pp. eabc8492
Author(s):  
Anoumid Vaziri ◽  
Morteza Khabiri ◽  
Brendan T. Genaw ◽  
Christina E. May ◽  
Peter L. Freddolino ◽  
...  
Keyword(s):  
Neural Plasticity ◽  
Molecular Mechanisms ◽  
Control Diet ◽  
Sweet Taste ◽  
Taste Perception ◽  
Epigenetic Mechanism ◽  
High Sugar ◽  
Epigenetic Regulator ◽  
Transcriptional Changes ◽  
Gustatory Neurons

Diets rich in sugar, salt, and fat alter taste perception and food preference, contributing to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here, we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of Drosophila melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.

scholarly journals Administration of interleukin-6 stimulates multilineage hematopoiesis and accelerates recovery from radiation-induced hematopoietic depression

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 472-480 ◽  
Author(s):  
ML Patchen ◽  
TJ MacVittie ◽  
JL Williams ◽  
GN Schwartz ◽  
LM Souza
Keyword(s):  
Bone Marrow ◽  
Interleukin 6 ◽  
Peripheral Blood ◽  
Progenitor Cell ◽  
White Cell ◽  
Red Cell ◽  
Hematopoietic Stem ◽  
Hematopoietic Recovery ◽  
Radiation Induced ◽  
Peripheral Blood White Cell

Abstract Hematopoietic depression and subsequent susceptibility to potentially lethal opportunistic infections are well-documented phenomena following radiotherapy. Methods to therapeutically mitigate radiation-induced myelosuppression could offer great clinical value. In vivo studies in our laboratory have demonstrated that interleukin-6 (IL-6) stimulates pluripotent hematopoietic stem cell (CFU-s), granulocyte-macrophage progenitor cell (GM-CFC), and erythroid progenitor cell (CFU-e) proliferation in normal mice. Based on these results, the ability of IL- 6 to stimulate hematopoietic regeneration following radiation-induced hematopoietic injury was also evaluated. C3H/HeN female mice were exposed to 6.5 Gy 60Co radiation and subcutaneously administered either saline or IL-6 (1,000 micrograms/kg) on days 1 through 3 or 1 through 6 postexposure. On days 7, 10, 14, 17, and 22, femoral and splenic CFU-s, GM-CFC, and CFU-e contents and peripheral blood white cell, red cell, and platelet counts were determined. Compared with saline treatment, both 3-day and 6-day IL-6 treatments accelerated hematopoietic recovery; 6-day treatment produced the greater effects. For example, compared with normal control values (N), femoral and splenic CFU-s numbers in IL-6-treated mice 17 days postirradiation were 27% N and 136% N versus 2% N and 10% N in saline-treated mice. At the same time, bone marrow and splenic GM-CFC values were 58% N and 473% N versus 6% N and 196% N in saline-treated mice; bone marrow and splenic CFU-e numbers were 91% N and 250% N versus 31% N and 130% N in saline-treated mice; and peripheral blood white cell, red cell, and platelet values were 210% N, 60% N, and 24% N versus 18% N, 39% N, and 7% N in saline- treated mice. These studies demonstrate that therapeutically administered IL-6 can effectively accelerate multilineage hematopoietic recovery following radiation-induced hematopoietic injury.

scholarly journals Epigenetic regulation of hematopoiesis by DNA methylation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Aniket V Gore ◽  
Brett Athans ◽  
James R Iben ◽  
Kristin Johnson ◽  
Valya Russanova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Dna Methyltransferase ◽  
Epigenetic Mechanism ◽  
Cell Fates ◽  
Hematopoietic Stem ◽  
Hematopoietic Development ◽  
Cell Type Specific ◽  
Cellular Identity

During embryonic development, cell type-specific transcription factors promote cell identities, while epigenetic modifications are thought to contribute to maintain these cell fates. Our understanding of how genetic and epigenetic modes of regulation work together to establish and maintain cellular identity is still limited, however. Here, we show that DNA methyltransferase 3bb.1 (dnmt3bb.1) is essential for maintenance of hematopoietic stem and progenitor cell (HSPC) fate as part of an early Notch-runx1-cmyb HSPC specification pathway in the zebrafish. Dnmt3bb.1 is expressed in HSPC downstream from Notch1 and runx1, and loss of Dnmt3bb.1 activity leads to reduced cmyb locus methylation, reduced cmyb expression, and gradual reduction in HSPCs. Ectopic overexpression of dnmt3bb.1 in non-hematopoietic cells is sufficient to methylate the cmyb locus, promote cmyb expression, and promote hematopoietic development. Our results reveal an epigenetic mechanism supporting the maintenance of hematopoietic cell fate via DNA methylation-mediated perdurance of a key transcription factor in HSPCs.

Enhanced Generation of Human Hematopoietic Stem/Progenitor Cells From ES and Patient Derived IPS Cells Using a Novel Compound Screen

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1294-1294
Author(s):  
Roger Emanuel Rönn ◽  
Roksana Moraghebi ◽  
Carolina Guibentif ◽  
Niels-Bjarne Woods
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Hematopoietic Cells ◽  
Ips Cells ◽  
Cell Generation ◽  
P Value ◽  
Hematopoietic Stem ◽  
Compound A

Abstract Abstract 1294 The ability to generate hematopoietic stem and progenitor cells from patient derived induced pluripotent stem (iPS) cells, would enable the generation of an unlimited supply of HLA matched transplantable cells for the treatment of both hematological disorders and malignancies. The goal of this project is to identify novel pathways involved in hematopoietic stem and progenitor cell generation and expansion from human ES and iPS cells. By using a small molecule compound library with our optimized iPS-2-blood lineage differentiation protocol, we have identified two novel chemical compounds that specifically enhance the generation of phenotypic adult hematopoietic stem cells. Compound A and compound B both enable increases of CD45/43+CD34+CD38-CD90+CD45RA- cells by 183+/−53%, n=5 and 275%, n=1, respectively. This is in comparison to DMSO carrier control wells, where the percentage of blood cells (CD45/43+) produced per total cells for these experiments was 73+/−2.9%, n=5. The increase in hematopoietic cell output using compound A was highly significant for the adult phenotypical hematopoietic stem cell fraction with a P-value of 0.03, n=5 (see Figure). Hematopoietic progenitor, CD45/43+ CD34+, counts were also slightly increased for compound A and B at 129+/−32%, n=5 and at 211%, n=1, respectively. Interestingly, no statistically significant increase in the number of total blood CD45/43+ cells was detected at the time of harvest, with either compound; at 108% +/− 8.4%, n=5, for compound A, and 164%, n=1, for compound B. In addition to the improvements, as measured by FACS, compounds A and B both increased the numbers of clonogenic progenitors as measured by CFU-assay, allowing for a 241+/−67%, n=4, and 443%, n=1, increase in total hematopoietic colony counts, respectively. These results identify 2 novel compounds with the ability to expand the more primitive fractions of hematopoietic cells with preferential expansion of the most primitive fraction of hematopoietic cells derived from human ES and iPS lines. We are currently performing transplantation experiments with cells generated using these compounds to assess their repopulating potential. Further studies are being performed to investigate the molecular mechanisms of these compounds for hematopoietic stem and progenitor cell generation from ES and iPS cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence

2020 ◽  
Vol 21 (23) ◽  
pp. 9130
Author(s):  
Anna Isermann ◽  
Carl Mann ◽  
Claudia E. Rübe
Keyword(s):  
Electron Microscopy ◽  
Dna Damage ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
Histone Variant ◽  
Epigenetic Mechanism ◽  
Premature Senescence ◽  
Biological Phenomena ◽  
Radiation Induced ◽  
Secretory Phenotype

Irreparable double-strand breaks (DSBs) in response to ionizing radiation (IR) trigger prolonged DNA damage response (DDR) and induce premature senescence. Profound chromatin reorganization with formation of senescence-associated heterochromatin foci (SAHF) is an essential epigenetic mechanism for controlling the senescence-associated secretory phenotype (SASP). To decipher molecular mechanisms provoking continuous DDR leading to premature senescence, radiation-induced DSBs (53BP1-foci) and dynamics of histone variant H2A.J incorporation were analyzed together with chromatin re-modeling in human fibroblasts after IR exposure. High-resolution imaging by transmission electron microscopy revealed that persisting 53BP1-foci developed into DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), consistently located at the periphery of SAHFs. Quantitative immunogold-analysis by electron microscopy revealed that H2A.J, steadily co-localizing with 53BP1, is increasingly incorporated into DNA-SCARS during senescence progression. Strikingly, shRNA-mediated H2A.J depletion in fibroblasts modified senescence-associated chromatin re-structuring and abolished SASP, thereby shutting down the production of inflammatory mediators. These findings provide mechanistic insights into biological phenomena of SASP and suggest that H2A.J inhibition could ablate SASP, without affecting the senescence-associated growth arrest.

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