Mitochondria iron transporter ABCB8 contributes to -7/del(7q) leukemia through regulating histone methylation
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PROVIDER: PRJNA1248888 | ENA |
REPOSITORIES: ENA
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Project description:Chromosome deletions are common in human cancers and often correlate with poor prognosis. Tumor suppressor genes are enriched in these deleted regions, yet their functional roles remain understudied, as their alterations typically involve copy number loss rather than mutations. Focusing on the commonly deleted 7q36 region in myeloid malignancies, we performed an sgRNA library screen and identified candidate genes whose loss disrupts hematopoietic stem and progenitor cell (HSPC) differentiation. Among these, ABCB8, encoding a mitochondrial iron transporter, was found to promote acute myeloid leukemia (AML) progression when combined with Trp53 and Nf1 loss. Mechanistically, ABCB8 deficiency impairs iron-dependent histone demethylase KDM6A activity, leading to differentiation blockade. Iron supplementation partially rescued this defect. Notably, KMT2C, another 7q36-located TSG and core COMPASS-like complex component, cooperated with ABCB8 loss to exacerbate differentiation arrest and leukemogenesis. Strikingly, ABCB8-deficient or del(7q) leukemia cells were vulnerable to ABCB8 restoration or EZH2 inhibition, suggesting therapeutic strategies. Our study uncovers a link between mitochondrial iron homeostasis, epigenetic regulation, and 7q deletion-driven leukemogenesis.
2025-04-14 | GSE294258 | GEO
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.
2019-07-26 | GSE118372 | GEO
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.
2019-07-26 | GSE118377 | GEO
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. Keywords: uterine leiomyomata, fibroids, del(7)(q22q32), gene expression, aCGH, microarray
2009-08-17 | GSE12814 | GEO
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.
2009-08-22 | E-GEOD-12814 | biostudies-arrayexpress
Project description:Aberrant DNA methylation is a hallmark of cancer but mechanisms contributing to the abnormality remain elusive. Here, we report that most of lung cancer cell lines tested expressed predominantly ∆DNMT3B-del whereas normal bronchial epithelial cells expressed equal quantities of ∆DNMT3B and ∆DNMT3B-del. We demonstrate biological impacts of ∆DNMT3B4-del, a ∆DNMT3B-del isoform, in a transgenic mouse model. Expression of ∆DNMT3B4-del in the mouse lungs resulted in an increased global DNA hypomethylation, focal DNA hypermethylation, epithelial hyperplastia and tumor formation when challenged with a tobacco carcinogen. In patients with non-small cell lung cancer, 83% of the primary tumors expressed predominantly ∆DNMT3B-del. Our results demonstrate ∆DNMT3B4-del as a critical factor in developing aberrant DNA methylation during lung tumorigenesis.
2017-02-09 | GSE68922 | GEO
Project description:Loss of all or part of chromosome 7 [-7/del(7q)] is recurrent in myeloid neoplasms and associated with a poor response to chemotherapy. Chromosome 7-encoded genes that drive drug resistance and the consequences of combinatorial 7q tumor suppressor gene loss have remained unclear, the latter question being largely due to the challenges of modeling aneuploidy. Here, we use in silico datamining to uncover 7q genes involved in chemotherapy resistance. We establish murine models of del(7q) clonal hematopoiesis and drug resistance with multiplex CRISPR-Cas9-mediated inactivation of four genes, Cux1, Ezh2, Kmt2c, and Kmt2e. Post-genotoxic exposure, combined deficiency of Cux1 and Ezh2 preferentially promotes clonal myeloid expansion in vivo, with compounding defects in DNA damage response and repair. Transcriptome analysis reveals combined Cux1 and Ezh2 loss recapitulates -7 patient gene signatures and defective DNA damage response pathways, to a greater extent than single gene loss. This work reveals a genetic interaction between CUX1 and EZH2, and sheds light on how -7/del(7q) contributes to leukemogenesis and drug resistance characteristic of these adverse-risk neoplasms. These data support the concept of 7q as a contiguous gene syndrome region, in which combined loss of multiple gene drives pathogenesis.
2025-01-01 | GSE266586 | GEO
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.
2014-03-19 | GSE54313 | GEO
Project description:Polyamines are aliphatic polycations that have emerged as important determinants of cell growth and viability in rapidly proliferating cells, including in the pathogenic protozoan parasite Leishmania donovani. In L. donovani, the polyamine spermidine is synthesized by the successive conversion of ornithine into putrescine (catalyzed by ornithine decarboxylase or ODC) and putrescine into spermidine (catalyzed by spermidine synthase or SPDSYN). Deletion of either ODC (del-odc) or SPDSYN (del-spdsyn) from the L. donovani genome renders these parasites auxotrophic for polyamines and these mutants are impaired in their ability to survive both in culture and within the mammalian host without the addition of exogenous polyamine supplementation. Significantly, del-odc parasites immediately cease proliferation after putrescine is removed from the culture media and perish within two weeks, while spermidine starved del-spdsyn mutants, which retain intracellular putrescine pools, show a slow-growth phenotype, and persist for several weeks in culture. To elucidate the key differences within the proteome of putrescine-starved del-odc cells and spermidine-starved del-spdsyn parasites, a shotgun quantitative proteomics approach was undertaken using TMT labeling and LC-MS/MS analysis. Briefly, three biological replicates each for mid-log phase del-odc and del-spdsyn promastigotes grown in the presence of exogenous putrescine (for del-odc) or spermidine (for del-spdsyn) supplementation were washed to remove the exogenous polyamine supplementation and incubated in polyamine-free media. At 24 and 48 h, cells from each biological replicate were isolated and prepared for tandem mass tag (TMT) labeling and downstream LC-MS/MS analyses. Peptides were identified using a database generated from the reference genome of L. donovani BPK282A1 strain. Changes in relative protein abundance for the polyamine-starved del-odc and del-spdsyn cell lines at 24 and 48 h were calculated by comparing aggregate total reporter ion intensities for each protein to that of the corresponding polyamine-supplemented 0-h timepoint.
2022-08-29 | PXD036349 | Pride
Project description:Monosomy 7 and del(7q) are among the most common and poorly understood genetic alterations in myelodysplastic neoplasms and acute myeloid leukemia. Chromosome band 7q22 is a minimally deleted segment in myeloid malignancies with a del(7q). However, the rarity of “second hit” mutations supports the idea that del(7q22) represents a contiguous gene syndrome. We generated mice harboring a 1.5 Mb germline deletion of chromosome band 5G2 syntenic to human 7q22 that removes Cux1 and 27 additional genes. Hematopoiesis is perturbed in 5G2+/del mice but they do not spontaneously develop hematologic disease. Whereas alkylator exposure modestly accelerated tumor development, the 5G2 deletion did not cooperate with KrasG12D, NrasG12D, or the MOL4070LTR retrovirus in leukemogenesis. 5G2+/del mice are a novel platform for interrogating the role of hemopoietic stem cell attrition/stress, cooperating mutations, genotoxins, and inflammation in myeloid malignancies characterized by monosomy 7/del(7q).
2025-01-22 | GSE254037 | GEO