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Gene expression data of serially sorted primary AML patient blasts prior and after treatment with the DNMT inhibitor decitabine (DAC)

ABSTRACT: DNMT inhibitors (DNMTi) are finally approved for AML/MDS, also based on their activity in patients with high-risk cytogenetics (often monosomal karyotype) such as -5/del(5q) or -7/del(7q), often - but not always - harboring TP53-mutations. Several studies provided evidence for aberrant hypermethylation/silencing on monoallelic gene loci, including tumor suppressor genes. We hypothesized that transcriptional repression on monosomal gene loci may be preferentially reversed by DNMTi. Using an unbiased RNA-seq approach we aimed to identify preferentially regulated genes in cells monoallelic for chromosome 7q. We validated these findings in serially sorted primary AML patient blasts at day 0 and day 8 of DNMTi treatment (within the DECIDER trial).

ORGANISM(S): Homo sapiens

PROVIDER: GSE138696 | GEO | 2021/03/09

REPOSITORIES: GEO

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Copy-number profiling by SNP array of 4 acute myeloid leukemia (AML) cell lines

Project description:DNMT inhibitors (DNMTi) are finally approved for AML/MDS, also based on their activity in patients with high-risk cytogenetics (often monosomal karyotype) such as -5/del(5q) or -7/del(7q), often - but not always - harboring TP53-mutations. Several studies provided evidence for aberrant hypermethylation/silencing on monoallelic gene loci, including tumor suppressor genes. We hypothesized that transcriptional repression on monosomal gene loci may be preferentially reversed by DNMTi. Using an unbiased RNA-seq approach we aimed to identify preferentially regulated genes in cells monoallelic for chromosome 7q.

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Transcriptome profiling by RNA-sequencing of the AML cell lines UCSD-AML1 and ELF-153.

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Expression analysis of Mll3 knockdown p53-/- HSPC vs. control p53-/- HSPC

Project description:Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of specific tumor suppressors on 7q remains elusive. Using RNAi and CRISPR/Cas9 approaches, we show that a ~50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3 suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor, and suggests a therapeutic option for this aggressive disease.

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Expression analysis of Mll3 knockdown p53-/- HSPC vs. control p53-/- HSPC

2014-03-19 | E-GEOD-54313 | biostudies-arrayexpress

Methylation data of serially sorted primary AML patient blasts prior and after treatment with the DNMT inhibitor decitabine (DAC)

Project description:The therapeutic effect of DNA-hypomethylating agents (HMAs) in AML/MDS is discussed to be via its effects on aberrant gene silencing by reactivation (e.g. through promoter demethylation). While this has been broadly studied in cell line models, only very few studies have addressed the global effects of HMAs in primary blasts serially isolated from AML patients (pts) undergoing HMA treatment (Claus et al., Leuk. Res. 2013, Klco et al., Blood 2013, Welch et al., N. Engl. J. Med. 2016). We therefore conducted prospective serial methylome and transcriptome analyses on AML blasts from pts of the DECIDER trial (NCT00867672), hypothesizing that both random and non-random effects of the HMA may be observed in vivo.

2023-04-24 | GSE175758 | GEO

Gene expression data of serially sorted primary AML patient blasts prior and after treatment with the DNMT inhibitor decitabine (DAC)

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The effect of spontaneous acquisition of an extra chromosome 7 for engineered del(7q) on induced pluripotent stem cells (iPSCs) derived from patients with Shwachman Diamond Syndrome (SDS).

Project description:Monosomy 7 or deletion of 7q (del(7q)) frequently arise in inherited and acquired bone marrow failure, and are associated with progression to high grade Myelodysplastic Syndrome (MDS) and acute leukemia. Current non-transplant approaches to treat marrow failure may be complicated by potential stimulation of clonal outgrowth. To study the biological consequences of del(7q) within the context of a failing marrow, we utilized induced pluripotent stem cells (iPSCs) derived from patients with Shwachman Diamond Syndrome (SDS) and genomically engineered a deletion of (7q). Deletion of 7q failed to confer a relative fitness advantage in either pluripotent SDS iPSC or in iPSC-derived SDS CD34+ cells. The TGF-beta pathway was the top differentially regulated pathway in transcriptome analysis with the TGF pathway found activated in SDS-iPSCs, compared to SDS-del(7q) iPSCs. Increased phosphorylation of SMAD2 in SDS-iPSCs was reduced following del(7q) and increased upon restoration of 7q diploidy, in support of an effect of 7q dosage on the activation status of the TGF-beta pathway in SDS. Inhibition of the TGF-beta pathway rescued hematopoiesis in SDS-iPSCs and in primary bone marrow cells from SDS patients without improving hematopoiesis of the SDS-del(7q) cells. Together, these results utilizing an iPSC model of MDS in BMF identified a targetable vulnerability for potential therapeutic strategies to ameliorate bone marrow failure without promoting outgrowth of the del7q clone.

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The effect of engineered del(7q) on induced pluripotent stem cells (iPSCs) derived from patients with Shwachman Diamond Syndrome (SDS).

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Spectrum of Mutations in Myeloid Neoplasms

Project description:Patients with myeloid malignancies bearing high-risk cytogenetic abnormalities lack effective therapies and have a poor overall survival. -7/del(7q) is identified in half of high-risk myeloid neoplasms. We recently identified CUX1 to be a haploinsufficient myeloid tumor suppressor gene located within the commonly deleted segment of 7q22. Here we identify the spectrum of somatic mutations that co-occur with loss of CUX1 and chromosome 7 in patients with de novo acute myeloid leukemia (AML) or a therapy-related myeloid neoplasm. -7/del(7q) leukemias have a distinct mutational profile characterized by low frequencies of alterations in major leukemogenic pathways, including genes encoding transcription factors, cohesin, and DNA-methylation-related proteins. In contrast, RAS pathway activating mutations occurred in 40% of -7/del(7q) samples, a significantly higher frequency than other AMLs and higher than previously reported. As targeted therapeutics advance, our data provide guidance for which pathways are most relevant in the treatment of adverse-risk myeloid leukemia.

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Transcription profiling of human uterine leiomyomata - identifying the molecular signature of the interstitial del(7q) subgroup using a paired analysis

Project description:Uterine leiomyomata (UL), the most common neoplasm in reproductive-age women, have recurrent cytogenetic abnormalities including del(7)(q22q32). To develop a molecular signature, matched del(7q) and non-del(7q) tumors identified by FISH or karyotyping from 11 women were profiled with expression arrays. Our analysis using paired t-tests demonstrates this matched design is critical to eliminate confounding effects of genotype and environment that underlie patient variation. A gene list ordered by genome-wide significance showed enrichment for the 7q22 target region. Modification of the gene list by weighting each sample for percent of del(7q) cells to account for the mosaic nature of these tumors further enhanced the frequency of 7q22 genes. Pathway analysis revealed two of the 19 significant functional networks were associated with development and the most represented pathway was protein ubiquitination, which can influence tumor development by stabilizing oncoproteins and destabilizing tumor suppressor proteins. Array CGH (aCGH) studies determined the only consistent genomic imbalance was deletion of 9.5 megabases from 7q22-7q31.1. Combining the aCGH data with the del(7q) UL mosacism-weighted expression analysis resulted in a list of genes that are commonly deleted and whose copy number is correlated with significantly decreased expression. These genes include the proliferation inhibitor HPB1, the loss of expression of which has been associated with invasive breast cancer, as well as the mitosis integrity-maintenance tumor suppressor RINT1. This study provides a molecular signature of the del(7q) UL subgroup and will serve as a platform for future studies of tumor pathogenesis. Experiment Overall Design: Matched del(7q) and non-del(7q) tumors identified by FISH or karyotyping from each of eleven woman were profiled using Affymetrix GeneChip U133 Plus 2.0 oligonucleotide gene expression arrays.

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