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 Regulation of gene transcription by Polycomb proteins

2015 ◽  
Vol 1 (11) ◽  
pp. e1500737 ◽  
Author(s):  
Sergi Aranda ◽  
Gloria Mas ◽  
Luciano Di Croce
Keyword(s):  
Gene Transcription ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Mechanisms Of Action ◽  
Polycomb Group ◽  
Chromatin Conformation ◽  
Polycomb Proteins ◽  
Positional Identity ◽  
And Function

The Polycomb group (PcG) of proteins defines a subset of factors that physically associate and function to maintain the positional identity of cells from the embryo to adult stages. PcG has long been considered a paradigmatic model for epigenetic maintenance of gene transcription programs. Despite intensive research efforts to unveil the molecular mechanisms of action of PcG proteins, several fundamental questions remain unresolved: How many different PcG complexes exist in mammalian cells? How are PcG complexes targeted to specific loci? How does PcG regulate transcription? In this review, we discuss the diversity of PcG complexes in mammalian cells, examine newly identified modes of recruitment to chromatin, and highlight the latest insights into the molecular mechanisms underlying the function of PcGs in transcription regulation and three-dimensional chromatin conformation.

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 The correlation between lncRNAs and Helicobacter pylori in gastric cancer

2019 ◽  
Vol 77 (9) ◽  
Author(s):  
Narges Dastmalchi ◽  
Seyed Mahdi Banan Khojasteh ◽  
Mirsaed Miri Nargesi ◽  
Reza Safaralizadeh
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Molecular Mechanisms ◽  
Gastrointestinal Diseases ◽  
Mechanisms Of Action ◽  
Molecular Pathways ◽  
Gastric Diseases ◽  
Non Coding Rnas ◽  
H Pylori ◽  
The Relationship

ABSTRACT Helicobacter pylori infection performs a key role in gastric tumorigenesis. Long non-coding RNAs (lncRNAs) have demonstrated a great potential to be regarded as effective malignancy biomarkers for various gastrointestinal diseases including gastric cancer (GC). The present review highlights the relationship between lncRNAs and H. pylori in GC. Several studies have examined not only the involvement of lncRNAs in H. pylori-associated GC progression but also their molecular mechanisms of action. Among the pertinent studies, some have addressed the effects of H. pylori infection on modulatory networks of lncRNAs, while others have evaluated the effects of changes in the expression level of lncRNAs in H. pylori-associated gastric diseases, especially GC. The relationship between lncRNAs and H. pylori was found to be modulated by various molecular pathways.

scholarly journals Should the BCRA1/2-mutations healthy carriers be valid candidates for hematopoietic stem cell donation?

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Alberto Fresa ◽  
Simona Sica
Keyword(s):  
Hematological Malignancies ◽  
Conditioning Regimen ◽  
Stress Factors ◽  
Brca Mutations ◽  
Hematopoietic Stem ◽  
Mutational Status ◽  
Stem Cell Donation ◽  
Radiation Treatments ◽  
Healthy Carriers

AbstractIt’s still not clear whether the mutational status of BRCA-mutated healthy hematopoietic stem cells (HSCs) donors could have an impact on the engraftment. Comparing the studies present in literature, we focused on the correlation between BRCA mutations and the development of hematological malignancies and Fanconi anemia (FA); then, we explored HSCs types, frequencies, and functions in the presence of BRCA mutations, as well as the reconstitution of hematopoiesis after chemotherapy and radiation treatments. The role of BRCA mutations in the FA showed a possible involvement in the onset of the disease; the mutation carriers, indeed, did not show any sign of the typical phenotype of the FA. BRCA mutational status can be considered as a risk factor for hematological malignancies, but only for secondary malignancies and/or in the presence of bone marrow stress factors. Currently we don’t know if a conditioning regimen could be compensated by BRCA mutated HSCs, even if murine models tried to show the possible differences between fully mutated, haploinsufficient and normal HSCs. Thus, given the downregulating effect of the mutations on hematopoiesis, it could be questionable to use the HSCs of a BRCA-mutated donor in the presence of another available donor with the same compatibility.

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