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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)

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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

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PRC2-mediated apoptosis evasion is a therapeutic target of MDS/AML harboring inv(3)/t(3;3) and monosomy 7 (CUT&Tag)

Project description:Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) harboring both inv(3)/t(3;3) and monosomy 7 (-7) are highly aggressive myeloid cancers whose molecular pathogenesis and therapeutic vulnerability remain elusive. High throughput drug screens, CUT&Tag/RNA sequence and functional assays using human MDS/AML cells revealed that EZH2 inhibitors efficiently induce apoptosis preferentially in MDS/AML with inv(3)/t(3;3) and -7 through activation of GADD45γ-p38-p53 axis. EVI1 activated in 3q-rearranged MDS/AML was responsible for GADD45γ silencing by direct binding to its consensus sequence within GADD45γ promoter and recruitment of PRC2 complex via interaction with EZH2, which can be therapeutically targeted by EZH2 inhibition. MDS/AML with inv(3)/t(3;3) and -7 showed preferential sensitivity to EZH2 inhibition in both mouse model and patient samples. Thus, MDS/AML cells with inv(3)/t(3;3) and -7 possess apoptosis evasion mechanism through EVI1-PRC2-mediated repression of GADD45γ-p38-p53 axis, which is a potential therapeutic vulnerability in MDS/AML patients with these high-risk cytogenetic lesions.

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