PH treatment
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PROVIDER: PRJNA688796 | ENA |
REPOSITORIES: ENA
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Project description:We aim to compare the genomic discrepancies across de novo Ph+ ALL, Ph+ MPAL and Ph+ AML, three diseases characterized by the occurrence of BCR-ABL1 transcripts but showing varied immunophenotypes. The data we are now submitting is the genomic copy number variants of these three groups. The following is the abstract with associated manuscript. The chromosome abnormality of Philadelphia (Ph) is typically seen in de novo acute lymphoblastic leukemia (ALL). It has also been identified in mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) in the revisions to World Health Organization classification of myeloid neoplasms and actue leukemia. The discrepancies between these patients and potential mechanisms underlying differentiation fate of the leukemia cells remain poorly defined. We evaluated the clinical, genomic and transcriptomic features of Ph+ ALL, Ph+ MPAL and Ph+ AML by taking advantage of high-density genomic analysis, including next-generation sequencing array comparative genomic hybridization and gene expression profiling for transcriptomic analysis. Our results showed that the three cohorts demonstrated diversified clinical features. Ph+ ALL had the best response to induction therapy, with a complete remission (CR) rate of 93.5 and molecular response of 43.5%. Ph+ MPAL had a 90.0% CR rate but only 5.9% of molecular response. The CR rate of Ph+ AML was only 68.8%. Ph+ ALL was characterized by loss and mutations of B-cell development gene IKZF1 and PAX5, and frequent histone H3K36 trimethyltransferase SETD2 mutations. SETD2 mutations were detected in 11.3% of Ph+ ALL patients and predicted higher relapse rate. Ph+ MPAL and Ph+ AML featured high frequency of RUNX1 mutations. Further studies showed RUNX1-R177X mutation inhibited 32D cell differentiation induced by G-Csf, and cooperated with BCR-ABL1 to lead to myeloid differentiation arrest of human cord blood CD34+ cells. It is therefore presumed that these additional mutations work in synergy with BCR-ABL1 fusion gene to facilitate the development of Ph-positive acute leukemia in different immunophenotypic classifications.
2022-04-29 | GSE130484 | GEO
Project description:Differences in global levels of histone acetylation occur in normal and cancer cells, although the reason cells regulate these levels has remained unclear. Here we demonstrate a role for histone acetylation in regulating intracellular pH (pHi). As pHi decreases, histones are globally deacetylated by histone deacetylases (HDACs) and the released acetate anions are co-exported with protons out of the cell by monocarboxylate transporters (MCTs), preventing further reductions in pHi. Conversely, global histone acetylation increases at more alkaline pHi, such as when resting cells are induced to proliferate. Inhibition of HDACs or MCTs decreases acetate export and lowers pHi, particularly compromising pHi maintenance in acidic environments. Global deacetylation at low pH is reflected at a genomic level by decreased abundance and extensive redistribution of acetylation at promoters and intergenic regions. Thus acetylation of chromatin functions as a rheostat to regulate pHi with important implications for therapeutic use of HDAC inhibitors. To investigate the redistribution of H4K16ac throughout the genome upon treatment at pH 6.5
2012-11-04 | E-GEOD-40114 | biostudies-arrayexpress
Project description:Copy number variations of Ph+ ALL, Ph+ MPAL and Ph+ AML
| PRJNA540459 | ENA
Project description:Background: BCR-ABL1-like, or Ph-like acute lymphoblastic leukemia is characterized by a gene expression profile similar to BCR-ABL1 positive ALL, genetic alterations of lymphoid transcription factor genes, and poor outcome. Sequencing of small numbers of Ph-like ALL cases has identified genetic alterations activating kinase signaling suggesting Ph-like ALL may be amenable to treatment with tyrosine kinase inhibitors. However, the spectrum of genetic alterations in childhood and adult Ph-like ALL is incompletely understood. Methods: We performed genomic profiling of 1736 B-ALL cases and next-generation sequencing for 160 Ph-like cases. We examined the functional effects of chimeric fusion proteins in mouse cell lines. Results: The frequency of Ph-like ALL rose from 11% in children to 26% in young adults, and was associated with very poor outcome. Kinase-activating alterations were identified in 90% of Ph-like cases, most commonly fusions involving 10 kinase or cytokine receptor genes (ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B and TYK2), and mutations involving FLT3, IL7R and SH2B3. Expression of ABL1, ABL2, CSF1R and JAK2 fusions resulted in cytokine-independent proliferation of cell lines and activation of pSTAT5. Cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions were sensitive to dasatinib, and JAK2 fusions to ruxolitinib. Conclusions: Ph-like ALL is characterized by a diverse range of genomic alterations that converge on a limited number of kinase signaling pathways amenable to inhibition with currently available tyrosine kinase inhibitors. Trials identifying Ph-like ALL and testing the efficacy of tyrosine kinase inhibitor therapy are warranted
| EGAS00001000654 | EGA
Project description:Even after the development of tyrosine kinase inhibitors (TKIs), the long-term prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is still unsatisfactory, which is thought to be associated with the high incidence of genetic alterations of Ikaros family zinc finger 1 (IKZF1). Lenalidomide (LEN), a representative of immunomodulatory drugs (IMiDs), has been effectively used for the treatment of relapsed/refractory multiple myeloma (MM), and its cytotoxic effect was recently shown to be mediated, at least in part, by marked down-regulation of IKZFs 1 and 3 expression through the interaction with the receptor cereblon (CRBN) forming a part of the Cullin-RING E3 ubiquitin ligase. In the present study, we examined the effects of LEN on ALL cells with a variety of genetic alterations and found that Ph+ALL cells expressing a dominant-negative IKZF1 isoform Ik6 which lacks the CRBN binding site were specifically sensitive to LEN where accumulation of Ik6 with disappearance of functional IKZF1 isoforms and the abrupt fall from very high levels of IKZF3 expression were documented. To examine the effect of lenalidomide and/or imatinib treatment on Ph-positive ALL cells from the viewpoint of gene expression, we performed micro array analysis. Of importance, the induction of apoptosis of Ph+ALL cells, even with the T315I mutation of BCR-ABL, was enhanced when they were treated with TKI in the presence of LEN. This synergism between LEN and TKIs was demonstrated in the xenograft mice model. IMiDs, now called as CRBN modulators, should be an attractive approach for potentiating responsiveness of Ph+ALL cells to TKIs, and this drug repositioning certainly facilitates their long-term survival if the effective combination regimen is warranted.
2021-06-16 | GSE155597 | GEO
Project description:Cell-type specific transcriptional profiles were generated by FACS (Fluorescence Activated Cell Sorting) sorting of roots that express cell-type specific GFP-reporters. Five different GFP-reporter lines were used. FACS cell populations were isolated from roots grown under standard pH (pH 5.7) or roots that had been transfered to low pH (pH 4.6) media for 24 hours. Stress responses in plants are tightly coordinated with developmental processes, but the interaction between these pathways is poorly understood. Here we use genome-wide assays at high spatial and temporal resolution to understand the processes that lnk development and stress in the Arabidopsis root. Our meta-analysis finds little evidence for a universal stress response. Common stress responses appear to exists and, analagous to animal systems, many of them show cell-type specificity, suggesting a convergent evolutionary theme in multicellular organisms. Common stress responses may be mediated by cell identity regulators, as mutations in these genes resulted in altered responses to stress. Our results reveal surprising linkages between stress and development at cellular resolution, and show the power of multiple genome-wide datasets to elucidate biological processes.
2011-11-23 | GSE30095 | GEO
Project description:Plants live in soils that vary considerably, both spatially and over time, in terms of nutrient composition and pH. Consistently, plants have to recognize and adapt to these changes by altering their structure and metabolism. The goal of this array analysis is to characterize the global transcriptional response to external pH changes in roots, which to date is almost unexplored. Arabidopsis thaliana (Columbia-0) were grown in hydroponic cultures in basic nutrient solution. Two days before treatment the media was shifted to nutrient solution containing 5mM MES, pH 6. At the time of the treatment start (4 hours after light on) the plants were shifted to nutrient solutions of pH 4.5 and 6.0 (control). Root RNA samples from time point 1 and 8 hour after treatment start is used for array analyzes. Keywords: Expression profilling by array
2009-11-18 | GSE18982 | GEO
Project description:Aluminum (Al) is the most common metal in the Earth’s crust and Al toxicity is considered to be the most harmful abiotic stress in acidic soils that today comprise more than 50% of the world’s arable lands. The first symptom of Al toxicity is the reduction of root growth, resulting in decreased water and nutrients uptake, plant growth retardation, and finally, yield reduction. Barley (Hordeum vulgare L.), which is the fourth cereal crop in regards to cultivation area and production tonnage, belongs to crops most sensitive to toxic aluminum ions in low pH soils. We present the RNA-seq transcriptome analysis of root meristems of barley seedlings grown in hydroponics at optimal pH (6.0), low pH (4.0), and low pH with Al (10 µM of bioavailable Al3+ ions). Two independent experiments were conducted: with short-term (24 h) and long-term (7 days) Al treatment. Interestingly, in the short-term experiment, more genes were differentially expressed between root meristems grown at pH=6.0 and pH=4.0, than between those grown at pH=4.0 with and without Al treatment. The upregulated genes that were overrepresented at conditions of low pH, compared to optimal pH, were associated with response to oxidative stress, cell wall organization, and iron ion binding. Among genes downregulated by low pH were mainly those related to chromatin organization. These results show that low pH itself is a severe stress for barley plants. Among genes upregulated by short Al treatment, overrepresented were those related to response to stress condition and calcium ion binding. After 7 days of hydroponics, the number of DEGs between hydroponics at pH=4.0 and 6.0 were still high but lower than in the short-term experiment, which suggests that plants partially adapted to the low pH. Interestingly, 7 day Al treatment caused massive changes in the transcriptome profile compared to the condition of low pH alone. Over 4 000 genes were upregulated and almost 2 000 genes were downregulated by long-term Al stress. These DEGs were related to e.g. stress response, cell wall development and metal ion transport. Based on our results we can assume that both, Al3+ ions and low pH are harmful to barley plants.Additionally, we phenotyped in detail the root system of barley seedlings grown in the same hydroponic conditions for 7 days at pH=6.0, pH=4.0, and pH=4.0 with Al. The results correspond to transcriptomic data and show that low pH itself is a stress facor that causes a significant reduction of root growth and the addition of aluminum further increases this reduction. It should be underlined that in the acidic arable lands, plants are exposed simultaneously to both of these stresses (low pH and Al), as Al becomes soluble at pH below 5.5. The presented transcriptome analysis may help to find potential targets for breeding barley plants more tolerant to such conditions.
2021-02-23 | GSE167271 | GEO
Project description:Acidic tissue microenvironment is commonly found in a variety of pathophysiological conditions. GPR4 is a proton-sensing G protein-coupled receptor that is fully activated by acidic extracellular pH but has lesser activity at the physiological pH 7.4 and minimal activity at more alkaline pH. To determine the effects of GPR4 activation by acidosis on vascular endothelial cells, we examined the global gene expression of the acidosis response in primary human umbilical vein endothelial cells (HUVEC) with varying level of GPR4. HUVEC with endogenous or overexpressed GPR4 level (designated as HUVEC/Vector & HUVEC/GPR4 cells). Two treatment conditions: pH 6.4 vs. pH 8.4 for 5 h. Biological replicates: 4 HUVEC/Vector replicates (pH6.4 vs pH 8.4), and 4 HUVEC/GPR4 replicates (pH6.4 vs pH 8.4).
2013-04-25 | E-GEOD-40060 | biostudies-arrayexpress
Project description:Cell-type specific transcriptional profiles were generated by FACS (Fluorescence Activated Cell Sorting) sorting of roots that express cell-type specific GFP-reporters. Five different GFP-reporter lines were used. FACS cell populations were isolated from roots grown under standard pH (pH 5.7) or roots that had been transfered to low pH (pH 4.6) media for 24 hours. Stress responses in plants are tightly coordinated with developmental processes, but the interaction between these pathways is poorly understood. Here we use genome-wide assays at high spatial and temporal resolution to understand the processes that lnk development and stress in the Arabidopsis root. Our meta-analysis finds little evidence for a universal stress response. Common stress responses appear to exists and, analagous to animal systems, many of them show cell-type specificity, suggesting a convergent evolutionary theme in multicellular organisms. Common stress responses may be mediated by cell identity regulators, as mutations in these genes resulted in altered responses to stress. Our results reveal surprising linkages between stress and development at cellular resolution, and show the power of multiple genome-wide datasets to elucidate biological processes. 3 replicates for each of 5 cell types for low pH and standard pH (30 samples total).
2011-11-23 | E-GEOD-30095 | biostudies-arrayexpress