Copy number analysis in de novo and therapy-related myeloproliferative neoplasms
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE42482 | GEO | 2012/11/24
SECONDARY ACCESSION(S): PRJNA182107
REPOSITORIES: GEO
Similar Datasets
Project description:Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. We performed SNP array analysis on de novo and therapy-related myeloid neoplasms and identified a 2.17 Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage upon transplantation into immunodeficient mice. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms. We performed SNP-array analysis of 34 primary patient samples with de novo or therapy-related myeloid leukemia and one acute myeloid leukemia cell line, UoCM1. For patient samples, DNA was obtained from the white blood cells of bone marrow or peripheral blood leukemia specimens. Cytogenetic analysis revealed clonal -7/del(7q) in 17 of the cases.
2012-11-24 | E-GEOD-42482 | biostudies-arrayexpress
Project description:<p>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 <i>CUX1</i> 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 <i>CUX1</i> and chromosome 7 in patients with <i>de novo</i> 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. </p>
| phs000759 | dbGaP
Project description:-7/del(7q) is genetic event prevalent in high-risk myeloid neoplasms. For reasons that are unclear, gain-of-function mutations in the RAS pathway frequently co-occur with monosomy 7. Here we identify a genetic interaction between RAS and the 7q-encoded transcription factor, CUX1. Concomitant mutations in RAS genes and CUX1 are wide-spread across tumor types, suggesting cooperativity in tumorigenesis. To test this, we generated mice with oncogenic NrasG12D and Cux1 knockdown. Double mutant mice developed myeloid malignancies with higher penetrance and faster onset than either single allele alone, with leukemic transformation in one third of cases. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem and progenitor cells (HSPCs). Reciprocally, CUX1 knockdown amplifies RAS signaling through decreased transcriptional expression of negative regulators of RAS and PI3K signaling. Accordingly, NrasG12D;Cux1-knockdown HSPCs have heighted growth factor-sensitivity and downstream RAS pathway activation. Double mutant HSPCs were responsive to PIK3 or MEK inhibition, suggesting that these may be promising therapeutic targets in patients with 7/del(7q) malignancies. Our results implicate the loss of CUX1 as the underlying explanation for the association of -7/del(7q) with oncogenic RAS. Furthermore, we report the unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.
2021-11-16 | GSE161614 | GEO
Project description:Monosomy 7 (-7) and del(7q) are high-risk cytogenetic abnormalities common in myeloid malignancies. We previously reported that CUX1, a homeodomain-containing transcription factor encoded on 7q22, is frequently inactivated in myeloid neoplasms, and CUX1 myeloid tumor suppressor activity is conserved from humans to Drosophila. CUX1-inactivating mutations are recurrent in clonal hematopoiesis of indeterminate potential as well as myeloid malignancies, in which they independently carry a poor prognosis. To determine the role for CUX1 in hematopoiesis, we generated 2 short hairpin RNA-based mouse models with ∼54% (Cux1mid) or ∼12% (Cux1low) residual CUX1 protein. Cux1mid mice develop myelodysplastic syndrome (MDS) with anemia and trilineage dysplasia, whereas CUX1low mice developed MDS/myeloproliferative neoplasms and anemia. In diseased mice, restoration of CUX1 expression was sufficient to reverse the disease. CUX1 knockdown bone marrow transplant recipients exhibited a transient hematopoietic expansion, followed by a reduction of hematopoietic stem cells (HSCs), and fatal bone marrow failure, in a dose-dependent manner. RNA-sequencing after CUX1 knockdown in human CD34+ cells identified a -7/del(7q) MDS gene signature and altered differentiation, proliferative, and phosphatidylinositol 3-kinase (PI3K) signaling pathways. In functional assays, CUX1 maintained HSC quiescence and repressed proliferation. These homeostatic changes occurred in parallel with decreased expression of the PI3K inhibitor, Pik3ip1, and elevated PI3K/AKT signaling upon CUX1 knockdown. Our data support a model wherein CUX1 knockdown promotes PI3K signaling, drives HSC exit from quiescence and proliferation, and results in HSC exhaustion. Our results also demonstrate that reduction of a single 7q gene, Cux1, is sufficient to cause MDS in mice.
2018-07-03 | GSE101300 | GEO
Project description:CUX1 is a homeodomain-containing transcription factor that is conserved, ubiquitous, and essential in vertebrates and invertebrates. CUX1 is mutated or deleted in high-risk myeloid neoplasms and solid tumors, resulting in haploinsufficiency and tumor growth. Here we provide the first analysis of endogenous, whole genome, CUX1 DNA binding. We demonstrate that CUX1 binds with transcriptional activators and cohesin at distal enhancers across three different human cell types. Haploinsufficiency of CUX1 altered the expression of a large number of genes, including cell cycle regulators, with concomitant increased cellular proliferation. Surprisingly, CUX1 occupancy decreased genome-wide in the haploinsufficient state, and binding site affinity did not correlate with differential gene expression. Instead, differentially expressed genes had multiple, low-affinity CUX1 binding sites, consistent with an analog model for CUX1 gene regulation. A machine-learning algorithm determined that chromatin accessibility, enhancer activity, and distance to the transcription start site are features of functional CUX1 DNA binding. Moreover, CUX1 is enriched at sites of DNA looping, and these loops connect CUX1 to the promoters of target genes. We propose that CUX1 is an analog transcription factor that regulates target genes through higher order genome architecture.
2017-03-29 | GSE92882 | GEO
Project description:Anemia is a significant cause of morbidity and mortality in myeloid malignances. Cytogenetic changes are recurrent within malignant hematopoietic stem and progenitor cells, yet their role in anemia pathogenesis remains unknown. One recurrent karyotypic abnormality in myeloid neoplasms is the deletion of part or all of chromosome 7 [-7/del(7q)], which harbors the transcription factor and tumor suppressor gene, CUX1. CUX1 knockdown mouse models develop myeloid disease similar to that seen in humans, including a spontaneous, cell intrinsic, and lethal anemia that develops with age. Here, we elucidate the cellular and molecular mechanisms by which CUX1 regulates erythropoiesis. We demonstrate CUX1 knockdown mice have an aberrant stress erythropoiesis response and decreased survival after acute anemia induction. CUX1 insufficient erythroblasts undergo accelerated cell cycling and increased apoptosis. In line with these phenotypes, transcriptome profiling indicates that CUX1-knockdown elicits increased proliferation and decreased erythroid differentiation gene signatures. ATAC-sequencing demonstrated dramatic, global chromatin opening in CUX1-knockdown erythroblasts. As measured by fluorescence lifetime imaging, this increased chromatin accessibility is concomitant with a disruption in nuclear condensation, which is normally requisite in mammalian erythroblasts for nuclear eviction and terminal differentiation. Finally, we show that CUX1 mediates chromatin compaction by promoting histone deacetylation. Thus, rather than a transcriptional role, our data implicate in an epigenetic regulatory role for CUX1 in erythropoiesis. Furthermore, these results suggest therapeutic targeting of epigenetic regulators, such as histone acetyl transferases, may have clinical benefit for the anemias associated with loss of CUX1.
2021-08-10 | GSE181626 | GEO
Project description:CUX1, a homeodomain-containing transcription factor, is recurrently deleted or mutated in multiple tumor types. In myeloid neoplasms, CUX1 deletion or mutation carries a poor prognosis. We have previously established that CUX1 functions as a tumor suppressor in hematopoietic cells across multiple organisms. Others, however, have described oncogenic functions of CUX1 in solid tumors, often attributed to truncated CUX1 isoforms, p75 and p110. Given the clinical relevance, it is imperative to clarify these discrepant activities. Herein, we sought to determine the CUX1 isoforms expressed in hematopoietic cells, and find that they express the full-length p200 isoform. Through the course of this analysis, we found no evidence of the p75 alternative transcript in any cell type examined. Using an array of orthogonal approaches, including biochemistry, proteomics, CRISPR/Cas9 genomic editing, and analysis of functional genomics datasets across a spectrum of normal and malignant tissue types, we found no data to support the existence of the CUX1 p75 isoform generated by an alternative transcriptional start site. Based on these results, prior studies of p75 require reevaluation, including the interpretation of oncogenic roles attributed to CUX1.
2022-02-17 | PXD027527 | Pride
Project description:The post-transcriptional control of mRNA stability plays a critical role in numerous biological functions, including the immune response, cell cycle regulation and DNA damage response. HNRNPA0, which encodes an RNA-binding protein shown to regulate transcript stability via binding to the AU-rich elements (AREs) of mRNAs, is located within the commonly deleted segment of 5q31.2 in therapy-related myeloid neoplasms (t-MNs) with a del(5q). We hypothesized that loss of HNRNPA0 leads to alterations in hematopoietic differentiation due to changes in the expression of its target AU-rich transcripts. Using RNAi interference to model Hnrnpa0 loss in primary murine cells and an experimental cell system, we found that reduced Hnrnpa0 expression leads to a shift from monocytic towards granulocytic differentiation. Microarray-based global expression profiling revealed that Hnrnpa0 knockdown disproportionally impacts ARE-containing transcripts and alters expression of myeloid specification genes. The biological importance of ARE-containing genes in myeloid neoplasms is further supported by changes in gene expression of ARE-mRNAs in t-MN del(5q) patients, predicted by pathway analysis to activate tumor growth. Together, our findings suggest that alterations in ARE-containing genes can positively regulate the cellular proliferation of del(5q) cells and implicate haploinsufficiency of HNRNPA0 as one of the key initiation mutations in the pathogenesis of t-MN. Gene expression profiling was performed on 38 single t-MN tumor samples. No control or reference samples were included.
2013-08-08 | E-GEOD-39991 | biostudies-arrayexpress
Project description:Therapy-related myeloid neoplasms (t-MN) are a high-risk, late effect in cancer survivors with poorly understood pathogenesis. It has been postulated that, in some cases, hematopoietic stem and progenitor cells (HSPCs) harboring mutations are selected for by cytotoxic exposures and transform. Here, we elucidate this model in the context of deficiency of CUX1, a transcription factor encoded on chromosome 7q. We report that CUX1 has a critical, early role in the DNA repair process in HSPCs. Mechanistically, CUX1 recruits the histone methyltransferase EHMT2 to DNA breaks to promote H3K27 methylation, phospho-ATM retention, subsequent γH2AX foci formation and propagation and, ultimately, 53BP1 recruitment. Despite significant unrepaired DNA damage sustained in CUX1-deficient murine HSPCs after cytotoxic exposures, they continue to proliferate and expand, mimicking clonal hematopoiesis in patients post-chemotherapy. As a consequence, preexisting CUX1 deficiency predisposes mice to highly penetrant and rapidly fatal therapy-related erythroleukemias. These findings establish the importance of epigenetic regulation of DNA repair and position CUX1 as a gatekeeper in myeloid transformation.
2021-05-03 | GSE154674 | 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