Landscape of gene mutations in Down syndrome-related myeloid disorders
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PROVIDER: EGAS00001000546 | EGA |
REPOSITORIES: EGA
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Project description:Acute megakaryoblastic leukemia (AMKL) is more frequently seen in Down syndrome patients, where it is often preceded by a transient myeloproliferative disorder (DS-TMD). The development of DS-TMD and DS-AMKL require not only the presence of the trisomy 21 but also that of GATA1 mutations. However, despite extensive studies into the genetics of DS-AMKL, not much is known about the epigenetic deregulation associated with this disease. In order to understand how epigenetic changes at the DNA methylation level contribute to DS leukemogenesis we performed DNA methylation profiling at different stages of development of this disease and analyzed the dynamics of epigenetic reprogramming. Early genome-wide epigenetic changes can be detected in trisomy 21 fetal liver mononuclear cells, even prior to the development of hematological abnormalities. These early changes are characterized by marked loss of DNA methylation at genes associated with regulation of key developmental processes. This first wave of aberrant DNA hypomethylation is followed by a second wave of epigenetic reprogramming detected in blast cells from DS-TMD and DS-AMKL, characterized by gains of methylation. This second wave of hypermethylation targets a distinct set of genes, preferentially affecting genes involved in hematopoiesis and regulation of cell growth and proliferation.
2013-08-19 | GSE46167 | GEO
Project description:The goal of this study is to define a gene expression signature unique to DS-AMKL (acute megakaryoblastic leukemia or FAB M7 leukemia). A similar study was done previously, but using unfractionated patient leukemic samples. In this study, we sorted megakaryocytic leukemia blasts from patients and then compared their gene expression signatures to those from similarly sorted blasts from patients with non-DS AMKL. This allowed us to identify a gene expression signature more unique to DS-AMKL samples.
2010-08-01 | GSE16677 | GEO
Project description:Acute megakaryoblastic leukemia (AMKL) is more frequently seen in Down syndrome patients, where it is often preceded by a transient myeloproliferative disorder (DS-TMD). The development of DS-TMD and DS-AMKL require not only the presence of the trisomy 21 but also that of GATA1 mutations. However, despite extensive studies into the genetics of DS-AMKL, not much is known about the epigenetic deregulation associated with this disease. In order to understand how epigenetic changes at the DNA methylation level contribute to DS leukemogenesis we performed DNA methylation profiling at different stages of development of this disease and analyzed the dynamics of epigenetic reprogramming. Early genome-wide epigenetic changes can be detected in trisomy 21 fetal liver mononuclear cells, even prior to the development of hematological abnormalities. These early changes are characterized by marked loss of DNA methylation at genes associated with regulation of key developmental processes. This first wave of aberrant DNA hypomethylation is followed by a second wave of epigenetic reprogramming detected in blast cells from DS-TMD and DS-AMKL, characterized by gains of methylation. This second wave of hypermethylation targets a distinct set of genes, preferentially affecting genes involved in hematopoiesis and regulation of cell growth and proliferation. DNA methylation profiles obtained at different stages of the development of Down syndrome AMKL and from CD41+ cells from partial trisomic mice
2013-08-19 | E-GEOD-46167 | biostudies-arrayexpress
Project description:The goal of this study is to define a gene expression signature unique to DS-AMKL (acute megakaryoblastic leukemia or FAB M7 leukemia). A similar study was done previously, but using unfractionated patient leukemic samples. In this study, we sorted megakaryocytic leukemia blasts from patients and then compared their gene expression signatures to those from similarly sorted blasts from patients with non-DS AMKL. This allowed us to identify a gene expression signature more unique to DS-AMKL samples. The leukemic blasts were sorted based on CD41, CD7, CD117, CD33, and CD34 antibodies as previously described (Klin. Padiatr. 217, 126-134).
2010-08-01 | E-GEOD-16677 | biostudies-arrayexpress
Project description:Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.
2016-06-17 | GSE83449 | GEO
Project description:Transient abnormal myelopoiesis (TAM) is a clonal pre-leukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, IL-2Rγnull mice. In serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. These results suggest that genetically heterogeneous subclones with varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from murine bone marrow (hCD45 sorted) or human peripheral blood samples. Copy number analysis of Affymetrix 500K SNP arrays was performed for xenografted TAM samples of 3 patients. There are also 3 samples from TAM patients in remission, which were used as references for copy number inference.
2013-03-01 | E-GEOD-44739 | biostudies-arrayexpress
Project description:Children with Down syndrome (DS) are at high risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (DS-AMKL). GATA1 gene mutations are detected in almost all TAM and DS-AMKL samples, leading to exclusive expression of short GATA1 protein (GATA1s) lacking of N-terminal domain (NTD). However, it remains to be clarified how GATA1s is involved with both disorders. To investigate how the loss of GATA1 NTD is involved in the molecular mechanisms of leukemogenesis in DS, we established the K562 GATA1s (K562-G1s) clones expressing only GATA1s by CRISPR/Cas9 genome editing. The K562-G1s clones expressed KIT at higher levels compared to the wild type K562 (K562-WT). With Chromatin-Immunoprecipitation (ChIP) studies, we found that both GATA1 and GATA1s were bound upstream of the KIT gene. To understand the status of the KIT gene in K562-WT and one of K562-G1 subclone, C1 #26, we also performed ChIP-seq of histone modifications. Although the ChIP-seq signals of C1 #26 tended to be slightly lower than those of K562-WT, the activation status of the KIT gene demonstrated by the histone modifications was not significantly different between K562-WT and C1#26. Chromosome conformation capture (3C)-modified proximity assays revealed the difference in the conformation of the KIT gene between the K562-WT and C1 #26. We found that the lack of the NTD of GATA1 altered the genomic structure of the KIT gene, resulting in dysregulation of KIT expression. These results suggest that the NTD of GATA1 is essential for proper genomic conformation and gene expression regulation of the KIT gene and that perturbation of this mechanism might be involved in the pathogenesis of TAM and DS-AMKL.
2022-11-29 | GSE159072 | GEO
Project description:Microarray gene expression profiling of lentivirus shRNA knockdown of the GATA1 gene in a DS AMkL cell line, CMK (harbors a mutated GATA1 gene and only expresses GATA1s).
2012-06-01 | GSE32388 | GEO
Project description:Down syndrome (DS), with trisomy of chromosome 21 (HSA21), is the commonest human aneuploidy. Pre-leukemic myeloproliferative changes in DS fetal livers precedes the acquisition of GATA1 mutations, transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL). Trisomy of the Erg gene is required for myeloproliferation in the Ts(1716)65Dn DS mouse model. We demonstrate here that genetic changes due trisomy of Erg lead to lineage priming of primitive and early multipotential progenitor cells in Ts(1716)65Dn mice, excess megakaryocyte-erythroid progenitors, and malignant myeloproliferation. Correlation of gene expression changes caused by Erg trisomy in Ts(1716)65Dn multilineage progenitor cells with those associated with trisomy 21 in human DS HSCs support a role for ERG as a regulator of hematopoietic lineage potential, trisomy of which drives pre-leukemic changes in DS fetal livers that predispose to subsequent DS-TMD and DS-AMKL.
2015-04-15 | E-MTAB-2574 | biostudies-arrayexpress
Project description:Gene expression profiling of Down Syndrome (DS)-AMKL and non-DS AMKL samples
| PRJNA122713 | ENA