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Affymetrix SNP array data for Genomic Instability and Myelodysplasia with Monosomy 7

ABSTRACT: Gene modified autologous hematopoietic stem cells (HSC) can provide significant clinical benefits to patients suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two patients treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both patients exhibited silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of EVI1. One patient died from overwhelming sepsis 27 months after gene therapy, whereas a second patient underwent an allogeneic HSC transplantation. Our data shows that forced overexpression of MDS1/EVI1 or EVI1 in human cells disrupts normal centrosome duplication, linking MDS1/EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression towards myelodysplasia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19523 | GEO | 2010/01/13

SECONDARY ACCESSION(S): PRJNA122235

REPOSITORIES: GEO

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Affymetrix SNP array data for Genomic Instability and Myelodysplasia with Monosomy 7

Project description:Gene modified autologous hematopoietic stem cells (HSC) can provide significant clinical benefits to patients suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two patients treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both patients exhibited silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of EVI1. One patient died from overwhelming sepsis 27 months after gene therapy, whereas a second patient underwent an allogeneic HSC transplantation. Our data shows that forced overexpression of MDS1/EVI1 or EVI1 in human cells disrupts normal centrosome duplication, linking MDS1/EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression towards myelodysplasia. Genomic copy number alterations were detected by analyzing the fluorescence signal intensities of each SNP on the GeneChip Human Mapping 100K array st (Affymetrix, Santa Clara, Ca) with the Copy Number Analyzer for Affymetrix GeneChip 100K arrays (CNAT) version 2.0. The log2 ratio of each SNP, the local averaged log2 signal ratio (averaged for 10 SNPs) and the inferred chromosome copy number according to the Hidden Markov Model (HMM) were calculated. Copy number analysis of Affymetrix 100K SNP arrays was performed for one young adult with the X-linked chronic granulomatous disease (X-CGD)

2010-01-12 | E-GEOD-19523 | biostudies-arrayexpress

Illumina GoldenGate Methylation array data for X-CGD patients and healthy controls

2009-12-17 | GSE19515 | GEO

Illumina GoldenGate Methylation array data for X-CGD patients and healthy controls

Project description:We report on the molecular and cellular events observed in two patients treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both patients exhibited silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of EVI1. In line with this observation, a genome wide methylation analysis of 807 cancer related genes revealed a DNA methylation pattern characteristic of MDS and AML patients. Genomic DNA was prepared from peripheral blood cells of patient 1 (d 0 and month 27) and 25 healthy controls including 12 males and 13 females. The GoldenGate Methylation Cancer Panel I array was used to compare methylation degree in 1.505 CpG sites from promoter regions or the first exon of 807 mostly cancer related genes between the patient 1 (d 0 and month 27) and 25 healthy controls.

2010-06-24 | E-GEOD-19515 | biostudies-arrayexpress

Expression data from human hematopoietic stem and progenitor compartments from patients with acute myeloid leukemia with monosomy 7 and healthy controls

Project description:We applied a novel approach of parallel transcriptional analysis of multiple, highly fractionated stem and progenitor populations in a genetically defined subset of AML (AML with monosomy 7). We isolated phenotypic long-term HSC (LT-HSC), short-term HSC (ST-HSC), and committed granulocyte-monocyte progenitors (GMP) from individual patients with AML, and measured gene expression profiles of each population, and in comparison to their phenotypic counterparts from age-matched healthy controls. Bone marrow samples from AML patients bearing monosomy 7 and age-matched healthy controls were used in this study. Hematopoietic stem and progenitor compartments were purified by multiparameter-high speed fluorescence-activated cell sorting (FACS) from CD34+ enriched bone marrow to isolate LT-HSC (Lin-/CD34+/CD38-/CD90+), ST-HSC (Lin-/CD34+/CD38-/CD90-), and GMP (Lin-/CD34+/CD38+/CD123+/CD45R+).

2012-09-05 | E-GEOD-35010 | biostudies-arrayexpress

Expression data from human hematopoietic stem and progenitor compartments from patients with acute myeloid leukemia with monosomy 7 and healthy controls

2012-09-05 | GSE35010 | GEO

Lung neutrophil subsets transcriptomes in WT and CGD mouse in response to fungal PAMPs stimulation

Project description:The leukocyte NADPH oxidase 2 (NOX2) regulates inflammation independent of its anti-microbial activity. Inherited defects in NOX2 lead to chronic granulomatous disease (CGD), associated with recurrent bacterial and fungal infections, often with excessive neutrophilic inflammation that results in significant inflammatory burden and tissue damage. We previously showed that excessive leukotriene B4 production by NOX2-deficient mouse neutrophils was a key driver of elevated lung neutrophil infiltration in the initial response to pulmonary challenge with the fungal particle zymosan (Song et al Blood 135, 891-903). We now identify IL-1β and downstream G-CSF as additional amplifying signals that augment and sustain neutrophil accrual in CGD mice. Neutrophils, delivered into the lung via LTB4, were the primary source of IL-1β within the airways, and their increased numbers in CGD lungs led to significantly elevated local and plasma G-CSF. Elevated G-CSF simultaneously promoted increased granulopoiesis and mobilized the release of higher numbers of an immature CD101neg neutrophil subset from the marrow, which trafficked to the lung and acquired a significantly more pro-inflammatory transcriptome in CGD mice compared to WT mice. Thus, neutrophil-produced IL-1β in the acute response to fungal cell walls acts sequentially but non-redundantly with LTB4 to deploy neutrophils and amplify inflammation in CGD mice. This illustrates how NOX2 plays a critical role in dampening multiple components of a feed-forward pipeline for neutrophil recruitment, and highlights NOX2 as a key regulator of neutrophil number and function at inflamed sites.

2022-09-05 | GSE198154 | GEO

Mutational analysis of a myelodysplasia cutis case

Project description:Mutational analysis of a myelodysplasia cutis case

| PRJEB40303 | ENA

Transcriptome analysis of nascent hematopoietic stem cells (HSCs) induced by the ectopic expression of Evi1

Project description:To examine the role of Evi1 in HSC specification, we generated Tie2-Cre::ROSA-Evi1 mice, which can induce Evi1 in endothelial cells. We observed five-fold increase of HSCs In Tie2-Cre::ROSA-Evi1 embryo. To characterize the induced HSCs in Tie2-Cre::ROSA-Evi1 embryos, we analyzed the gene expression profile of HSCs.

2022-06-22 | GSE190011 | GEO

Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct WHO recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2 enhancer (3q21) to MECOM (3q26) results in overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2 from the unaffected allele. The full-length MECOM transcript, MDS1-EVI1, is not expressed as the result of the 3q26 rearrangement. Besides the classical inv(3)/t(3;3), a number of other 3q26/MECOM rearrangements with poor treatment response have been reported in AML. Here we demonstrate, in a group of 33 AML patients with atypical 3q26 rearrangements, MECOM involvement with EVI1 overexpression, but no or low MDS1-EVI1 levels. Moreover, the 3q26 translocations in these AML patients often involve super-enhancers of genes active in myeloid development (e.g. CD164, PROM1, CDK6 or MYC). In more than 50% of these cases allele specific GATA2 expression was observed, either by copy number loss or by an unexplained allelic imbalance. Altogether, atypical 3q26 recapitulate the main leukemic mechanism of inv(3)/t(3;3) AML, namely EVI1 overexpression driven by enhancer hijacking, absent MDS1-EVI1 expression and potential GATA2 involvement. Therefore, we conclude that both atypical 3q26/MECOM and inv(3)/t(3;3) can be classified as a single entity of 3q26-rearranged AMLs. Routine analyses determining MECOM rearrangements, EVI1 and MDS1-EVI1 expression are required to recognize 3q-rearranged AML cases.

| EGAS00001004325 | EGA

Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia (RNA-Seq)

Project description:Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 at MECOM drive inv(3)/t(3;3) myeloid leukemias and revealed MECOM germline mutations in patients with MECOM-associated bone marrow failure syndromes. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 which is frequently present in inv(3)/t(3;3) AML and directly contributes to leukemic transformation. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21;26) allele hastened leukemogenesis in vivo. These data provide a mechanistic basis for the frequent co-occurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

2022-06-21 | GSE202208 | GEO

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