Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA208363 | ENA |
REPOSITORIES: ENA
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Project description:A comparison of global gene expression between rigorously defined stem and progenitor cells from patients with chronic myeloid leukaemia (CML) in chronic (CP), accelerated (AP) and blastic (BC) phase and similar populations isolated from normal volunteers.
2013-09-06 | GSE47927 | GEO
Project description:A comparison of global gene expression between rigorously defined stem and progenitor cells from patients with chronic myeloid leukaemia (CML) in chronic (CP), accelerated (AP) and blastic (BC) phase and similar populations isolated from normal volunteers. Cryopreserved CD34+ enriched cell populations obtained from patients with CML in CP, AP or BC at diagnosis prior to treatment -- or from normal volunteers -- were thawed and flow sorted into rigorously defined sub-populations (HSC, MPP, CMP, GMP and MEP -- using surface phenotype as described below). Total RNA was obtained and global gene expression measured following hybridisation to Affymetrix HuGene-1_0-st-v1 gene-chips. In total, 3 normal patient samples were compared with 6 CP, 4 AP and 2 BC samples. HSC, CMP, GMP and MEP populations were obtained from all specimens, MPP populations were obtained from normal, AP and BC specimens but not CP specimens.
2013-09-06 | E-GEOD-47927 | biostudies-arrayexpress
Project description:Chronic myeloid leukemia (CML) is a hematopoetic stem cell disease with distinct biological and clinical features. The biological foundation of the stereotypical progression from chronic phase through accelerated phase to blast crisis is poorly understood. We used DNA microarrays to compare gene expression in 91 cases of CML in chronic (42 cases), accelerated (17 cases), and blast phases (32 cases). Three thousand genes were found to be significantly (p<10-10) associated with the progression from chronic to blast phase. A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML from chronic advanced phase (accelerated and blast crisis) CML is a two-step rather than a three-step process, with new gene expression changes occurring early in accelerated phase before the accumulation of increased leukemia blast cells. The genetic signature of advanced phase CML is similar to that of normal CD34+ cells; however, progression also involved novel genes not expressed in normal CD34+ cells. Especially noteworthy is deregulation of the WNT/b-catenin pathway, the decreased expression of both JunB and Fos, and dysregulation of genes under the control of MZF1 and delta EF1 zinc finger transcription factors. Studies of CML patients who relapsed after initially successful treatment with imatinib mesylate demonstrated a gene expression pattern closely related to advanced phase disease. Take together, these data suggest that CML progression begins relative early and before clinical and pathological detection, and features distinct genetic differences compared to normal hematpoetic cells that might provide diagnostic and therapeutic targets. Samples from different phases of CML were hybridized against the pool of chronic phases of samples.
2010-06-11 | E-GEOD-4170 | biostudies-arrayexpress
Project description:Chronic myeloid leukemia (CML) is a hematopoetic stem cell disease with distinct biological and clinical features. The biological foundation of the stereotypical progression from chronic phase through accelerated phase to blast crisis is poorly understood. We used DNA microarrays to compare gene expression in 91 cases of CML in chronic (42 cases), accelerated (17 cases), and blast phases (32 cases). Three thousand genes were found to be significantly (p<10-10) associated with the progression from chronic to blast phase. A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML from chronic advanced phase (accelerated and blast crisis) CML is a two-step rather than a three-step process, with new gene expression changes occurring early in accelerated phase before the accumulation of increased leukemia blast cells. The genetic signature of advanced phase CML is similar to that of normal CD34+ cells; however, progression also involved novel genes not expressed in normal CD34+ cells. Especially noteworthy is deregulation of the WNT/b-catenin pathway, the decreased expression of both JunB and Fos, and dysregulation of genes under the control of MZF1 and delta EF1 zinc finger transcription factors. Studies of CML patients who relapsed after initially successful treatment with imatinib mesylate demonstrated a gene expression pattern closely related to advanced phase disease. Take together, these data suggest that CML progression begins relative early and before clinical and pathological detection, and features distinct genetic differences compared to normal hematpoetic cells that might provide diagnostic and therapeutic targets. Keywords: disease state analysis
2006-02-21 | GSE4170 | GEO
Project description:Comparison of gene expression profiles of CD34+ hematopoietic stem and progenitor cells from bone marrow of patients with untreated chronic myelogenous leukemia (CML) in chronic phase with those from bone marrow of healthy volunteers. Chronic myelogenous leukaemia (CML) is a malignant disorder of the hematopoietic stem cell, which is characterized by the reciprocal translocation between chromosomes 9 and 22 (t(9;22)(q34;q11)) The translocation results in the formation of the BCR-ABL fusion oncogene encoding a protein with constitutive activated tyrosine kinase activity which plays a central role in the pathogenesis of the disease. There are still several open questions with respect to BCR-ABL-induced malignant transformation. A large limitation of the existing data about BCR-ABL effects is that they are derived to a great proportion from human hematopoietic cell lines, BCR-ABL-transformed murine cell lines or fibroblasts and mouse models, which might not be representative for chronic phase CML. A suitable cell population for studies on CML biology are primary hematopoietic stem and progenitor cells from patients with CML. Therefore, we provide in this study a genome-wide expression signature of highly enriched CD34+ cells from bone marrow (BM) of untreated patients with CML in chronic phase. Gene expression profiles of immunomagnetically enriched BM CML CD34+ cells (n=9) were compared with those of normal BM CD34+ cells (n=8) using microarrays covering 8.746 genes. Total RNA was extracted, reversely transcribed, in vitro transcribed and labelled and hybridized to Affymetrix HG Focus Arrays. Following quality control and normalization differentially expressed genes were identified by significance analysis of microarrays (SAM). Comparing both groups 918 genes were significantly differentially expressed (q value <0.1%; fold change > 1.3). Several of the BCR-ABL-induced effects described in cell lines and BCR-ABL-transduced cells could also be found in primary CML progenitor cells as for example the transcriptional activation of the classical MAPK pathway and the PI3 kinase/AKT pathway and the down-regulation of the pro-apoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34+ cells were identified. These include an up-regulation of components of the TGFb signalling pathway and the non-canonical Wnt/Ca2+ pathway, a transcriptional activation of fetal haemoglobin genes and genes associated with early hematopoietic stem cells (HSC) such as HoxA9 and MEIS1 and up-regulation of genes involved in fatty acid metabolism, of the thrombin receptor PAR1 and the neuroepithelial cell transforming gene 1. Differential expression of differentiation-associated genes suggested an alteration of the composition of the CD34+ cell population in CML. This was confirmed by immunophenotypical subset analyses of chronic phase CML CD34+ cells showing an increase of erythroid progenitors and a decrease of granulocyte-macrophage progenitor cells while the proportion of HSC was similar in normal and CML CD34+ cells. In conclusion, our results give novel insights into the biology of CML hematopoietic stem and progenitor cells and could be the basis for identification of new targets for therapy.
2007-11-01 | E-GEOD-5550 | biostudies-arrayexpress
Project description:A characteristic of chronic phase CML is accumulation of mature cells in the peripheral blood. It has not been determined if this expansion is explained by the CD34+ cell subset composition. We conducted flowcytometry-based cell sorting to assess the CD34+ subset composition and to retrieve the respective cells. We found a significant increase in the proportion of MEP and a decrease of HSC and GMP in patients with chronic phase CML compared to their healthy counterparts. The absolute number of HSC was similar, whereas CMP, GMP and MEP were expanded 2.8- to 7.7-fold. Gene expression analysis of CD34+ cell subsets showed, that in contrast to the normal developmental hierachy, CML HSC have a transcriptional profile which is similar to CML progenitor subsets and healthy CMP. HSC in healthy individuals show greater distance to their more mature progeny within the developmental hierarchy. As the differences between CML and healthy controls were minor at the progenitor level, we focused on the further characterization of CML HSC. 614 genes were differentially expressed, including downregulation of genes involved in adhesion and migration, regulation of the stem cell pool, and differentiation. We also found abrogation of nuclear receptors NR4A1 and NR4A3, and decreased expression of c-Jun and JunB. Re-expression of c-Jun and JunB in CD34+ cells from CML patients was achieved by co-transfection of NR4A1 and NR4A3. Moreover, we functionally corroborated a decreased adhesion capacity of the CML HSC. Taken together, these findings help to explain the hematological phenotype of CML patients in chronic phase. Experiment Overall Design: CD34+ subsets of 6 patients with chronic phase CML and 5 healthy volunteers were analysed by means of gene expression profiling with the Affymetrix HU-133A 2.0 array
2009-01-13 | E-GEOD-11889 | biostudies-arrayexpress
Project description:The circRNAs of chronic myelelogenous leukemia (CML) accelerated phase and chronic phase (CP) were more obvious than normal subjects. QRT-PCR verified that the expressions of hsa_circ_0001523, hsa_circ_0006010 and hsa_circ_0066971 were significantly up-regulated, while the expressions of hsa_circ_000095, hsa_circ_0001801 and HSA_circ_0002903 were down-regulated in advanced patients. Bioinformatics analysis revealed that some dysregulated crRnas may be active in important biological pathways by acting as miRNA sponges during CML disease progression. These six circrnas have high diagnostic value. Our study confirms significant circrNA dysregulation in CML patients and describes a circrNA marker associated with CML disease progression.
2022-09-05 | GSE212254 | GEO
Project description:The resistance of CML leukemic stem cells (LSC) to tyrosine kinase inhibitor therapies targeting BCR-ABL leads to persistence of disease in most cases. We have identified novel putative therapeutic targets that are differentially expressed in CML LSCs compared to normal hematopoietic stem cells (HSC) by transciptional profiling of stem and progenitor cell populations from CML patients and normal donors. These data are used to obtain 97 genes that are differentially expressed in CML vs. normal stem and progenitor cells and 236 transcripts that show evidence of alternative exon usage in CML vs. normal stem cells. Bone marrow stem and progenitor cell fractions from 5 patients with newly diagnosed and untreated chronic phase CML and 5 healthy donors were analyzed. Contrasts between CML vs. normal stem and progenitors overall and CML vs. normal stem cells were performed using Partek Genomic Suite software. Genes with |log2(fold-change) > 1| and false discovery rate (FDR) of 0.05 were identified as significantly differentially expressed. To identify genes with evidence of alternative exon useage, contrasts between CML and normal stem cell populations were performed, and genes with an alternative splicing FDR of 0.01 were considered to be alternatively spliced.
2013-05-08 | E-GEOD-43754 | biostudies-arrayexpress
Project description:In comparing gene expression of normal and CML CD34+ quiescent (G0) and proliferating (G1/S/G2/M) cells, 292 genes were down-regulated and 192 genes were up-regulated in the CML G0 cells. The differentially expressed genes were grouped according to their reported functions and correlations were sought with biological differences previously observed between the same groups. The most apparent correlations include: i) Normal and CML G0 cells are more primitive than G1/S/G2/M cells; ii) CML G0 cells are in a more advanced stage of development and more poised to begin proliferating than normal G0 cells; iii) When CML G0 cells are stimulated to proliferate, they undergo further differentiation and maturation more rapidly than normal G0 cells, but both granulopoiesis and erythropoiesis are less efficient than normal; iv) Whereas normal G0 cells form only granulocyte/monocyte (GM) colonies when stimulated by cytokines, CML G0 cells consistently form a combination of GM and erythroid clusters and colonies; and v) Prominin-1 (CD133) is the gene most down-regulated in CML G0 cells and its down-regulation appears to be associated with the spontaneous formation of erythroid colonies by CML progenitors without EPO. The gene most over-expressed in CML G0 cells is LepR, but its role in contributing to the myeloid expansion and other abnormalities is unknown. It was hoped that LepR might serve as a therapeutic target, but leptin had no stimulatory or inhibitory effect on either normal or CML G0 cells, our attempts to make a specific LepR antibody were unsuccessful, and no other potentially targetable over-expressed surface antigens were identified. A total of eight patients diagnosed with Ph+ CML (three in accelerated phase and five in chronic phase) were used in this study. The CML samples were all obtained from patients hospitalized at the Memorial Sloan Kettering during the period 1990-2006. The four normal bone marrow samples were purchased from Cambrex (Cambrex Bio Science Rockland,Inc., Rockland, Maine 04841, USA).
2010-10-16 | E-GEOD-24739 | biostudies-arrayexpress
Project description:Little is known about the impact of DNA methylation on the evolution/progression of chronic myeloid leukemia (CML). We investigated the methylome of CML patients in chronic phase (CP-CML), accelerated phase (AP-CML) and blast crisis (BC-CML) as well as in controls by reduced representation bisulfite sequencing. While only ~600 differentially methylated CpG sites were identified in samples obtained from CP-CML patients compared to controls, ~6,500 differentially methylated CpG sites were found in cells from BC-CML patients. In the majority of affected CpG sites methylation was increased. In CP-CML patients who progressed to AP-CML/BC-CML, we identified up to 897 genes which were methylated at the time of progression but not at the time of diagnosis. Using RNA-sequencing, we observed downregulated expression of many of these genes in BC-CML compared to CP-CML-derived cells. Several of them are well-known tumor suppressor genes or regulators of cell proliferation. 5-aza-2 -deoxycytidine treatment of CML cells resulted in gene re-expression and in a dose-dependent cell growth reduction. Single nucleotide variants of certain epigenetic modifiers during CML progression were not found. Together, our results demonstrate that methylation changes occur frequently during CML progression and may provide a useful basis for revealing new targets of therapy in advanced CML.
2016-08-01 | E-MTAB-4333 | biostudies-arrayexpress