Dysregulated gene expression pathways in mice models of HR-MDS and AML post MDS mimic human disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE72934 | GEO | 2017/02/11
SECONDARY ACCESSION(S): PRJNA295371
REPOSITORIES: GEO
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Project description:In order to gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathway. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or –7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with –7/del(7q) by pathways involved in cell survival, whilst patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder thereby providing new targets for therapeutic intervention.
2010-03-13 | GSE19429 | GEO
Project description:In order to gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathway. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or â??7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with â??7/del(7q) by pathways involved in cell survival, whilst patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder thereby providing new targets for therapeutic intervention. 183 patients with MDS patients and 17 healthy controls were included in the study. Bone marrow samples were obtained and CD34+ cells isolated from MDS patients and healthy controls. Samples were hybridized to Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays
2010-03-24 | E-GEOD-19429 | biostudies-arrayexpress
Project description:Aplastic anaemia (AA) is a form of bone marrow failure (BMF) resulting in significant cytopenias and may progress with clonal evolution to myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). MicroRNA expression is dysregulated in MDS/AML but there are limited studies on its role in the pathogenesis of AA. Using stored BM samples (n=81) from 2006-2019 from 52 patients, we demonstrate key differences in miRNA expression between AA patients at diagnosis and de novo MDS patients (n=21). The five most significantly upregulated miRNA in MDS patients (downregulated in AA) were miR-130a-3p, miR-221-3p, miR-126-3p, miR-27b-3p and miR-196b-5p (adj p<0.001). However, at the time of AA clonal progression to secondary MDS/AML, no significant miRNA differences were identified suggesting that the underlying mechanistic pathways are similar between AA progression to MDS/AML and de novo MDS. At diagnosis, miR-127-3p, miR-1271-5p, miR-301b-5p, miR-3934-5p and miR-4531 (adj p=0.081) were upregulated in those whose AA eventually progressed in comparison to those without eventual clonal progression. Using KEGG pathway analysis derived from miRPathDBv2.0, cytokine-cytokine receptor interaction, TGF-, MAP kinase, prolactin, Hippo, neurotrophin and FOXO signalling pathways were enriched in AA patients with clonal progression to MDS/AML; these pathways were similarly enriched in the de novo MDS cohort. These studies highlight the differing miRNA expression profiles in AA and MDS and in AA clonal evolution to MDS/AML.
2023-09-02 | GSE242216 | GEO
Project description:Apc, a negative regulator of the canonical Wnt signaling pathway, is a bona-fide tumor suppressor whose loss of function results in intestinal polyposis. APC is located in a commonly deleted region on human chromosome 5q, associated with myelodysplastic syndrome (MDS) suggesting that haploinsufficiency of APC contributes to the MDS phenotype. Analysis of the hematopoietic system of mice with the Apcmin allele that results in a premature stop codon and loss of function, showed no abnormality in steady state hematopoiesis. Bone marrow derived from Apcmin mice showed enhanced repopulation potential, indicating of a cell intrinsic gain of function in the long-term hematopoietic stem cell (HSC) population. However, Apcmin bone marrow was unable to repopulate secondary recipients due to loss of the quiescent HSC population. Apcmin mice developed a myelodysplastic/ myeloproliferative phenotype. Our data indicate that Wnt activation through haploinsufficiency of Apc causes insidious loss of HSC function that is only evident in serial transplantation strategies. These data provide a cautionary note for HSC expansion strategies through Wnt pathway activation, provide evidence that cell extrinsic factors can contribute to the development of myeloid disease and indicate that loss of function of APC may contribute to the phenotype observed in patients with MDS and del(5q). LKS+ cells were isolated from Apcmin or WT mice using high-speed multiparameter flow cytometry. At least 2x104 cells per mouse were isolated with confirmed purity in excess of 90%. The cells were treated with RLT lysis buffer (Qiagen) containing beta-mercaptoethanol to stabilize RNA. RNA was extracted using Qiagen RNeasy Micro Kit according to manufacturers instruction. The RNA was amplified using a linear amplification protocol (Nugen Ovation V2 amplification system). cDNA was fragmented and biotinylated before hybridization onto Affymetrix mouse genome 430 2.0 Array chips
2010-02-21 | E-GEOD-20352 | biostudies-arrayexpress
Project description:Apc, a negative regulator of the canonical Wnt signaling pathway, is a bona-fide tumor suppressor whose loss of function results in intestinal polyposis. APC is located in a commonly deleted region on human chromosome 5q, associated with myelodysplastic syndrome (MDS) suggesting that haploinsufficiency of APC contributes to the MDS phenotype. Analysis of the hematopoietic system of mice with the Apcmin allele that results in a premature stop codon and loss of function, showed no abnormality in steady state hematopoiesis. Bone marrow derived from Apcmin mice showed enhanced repopulation potential, indicating of a cell intrinsic gain of function in the long-term hematopoietic stem cell (HSC) population. However, Apcmin bone marrow was unable to repopulate secondary recipients due to loss of the quiescent HSC population. Apcmin mice developed a myelodysplastic/ myeloproliferative phenotype. Our data indicate that Wnt activation through haploinsufficiency of Apc causes insidious loss of HSC function that is only evident in serial transplantation strategies. These data provide a cautionary note for HSC expansion strategies through Wnt pathway activation, provide evidence that cell extrinsic factors can contribute to the development of myeloid disease and indicate that loss of function of APC may contribute to the phenotype observed in patients with MDS and del(5q).
2010-02-16 | GSE20352 | GEO
Project description:Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies like MDS and AML. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146aKO), a commonly deleted gene in MDS and AML, cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO HSPCs expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146aKO/RUNX1mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.
2024-05-29 | GSE264052 | GEO
Project description:Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies like MDS and AML. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146aKO), a commonly deleted gene in MDS and AML, cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO HSPCs expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146aKO/RUNX1mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.
2024-05-29 | GSE264051 | GEO
Project description:To characterize the dysregulated MSCs in the murine MDS models, we performed a single-cell RNA sequence (scRNA-seq) analysis of FACS-sorted MSCs. The proportions of subclusters comprising MSCs were discrete between controls and MDS, and Osteolineage population was reduced in MDS compared with the control. In addition, Lepr+ mesenchymal population in MDS mice exhibited the remarkable reduction of skeletal stem marker Grem1 and MSC marker genes. This transcriptome analysis suggested that the osteolineage differentiation of MSCs is suppressed in vivo in the presence of MDS cells.
2022-10-01 | GSE199665 | GEO
Project description:An increasing body of work reveals aberrant hypermethylation of genes occurring in and potentially contributing to the pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDS), are responsive to DNA methyltransferase inhibitors. In order to determine the extent of promoter hypermethylation in such tumors we compared the distribution of DNA methylation of 14,000 promoters in MDS and secondary AML patients enrolled in a phase I trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34+ bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34+ bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. Keywords: DNA methylation profiling Direct comparison of DNA methylation in bone marrow samples from patients with Myelodysplastic syndrome or secondary Acute Myeloid Leukemia (AML) at baseline and after in vivo treatment with 5-azacytidine + etinostat. A comparison to de novo normal karyotype AML was also performed. Two control groups were included: one consisting of 8 CD34+ bone marrow samples from healthy donors and a second one consisting of matched CD34+ and CD34- fractions from the bone marrows of 4 healthy donors.
2010-05-15 | E-GEOD-17328 | biostudies-arrayexpress
Project description:To characterize the molecular changes in myelodysplastic syndromes (MDS) and to explore novel genetic abnormalities occurring in these disorders through a genome-wide study in a series of MDS and MDS/MPN patients. A total of 285 abnormalities were identified in 71 patients. Three high-risk MDS cases displayed chromothripsis. In addition, cryptic deletions were identified in genomic regions where MDS-related genes, such as DNMT3A (2p23.3), TET2 (4q24), RUNX1 (21q22) and BCOR (Xp11.4), are located.
2016-11-21 | GSE67682 | GEO