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Knockdown of Hnrnpa0, a del(5q) Gene, Alters Myeloid Cell Fate in Murine Cells through Regulation of AU-rich Transcripts

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Shann-Ching Chen

PROVIDER: E-GEOD-39991 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Knockdown of Hnrnpa0, a del(5q) Gene, Alters Myeloid Cell Fate in Murine Cells through Regulation of AU-rich Transcripts

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.

2013-08-08 | GSE39991 | GEO

Cytotoxic therapy-induced effects on both hematopoietic and marrow stromal cells promotes therapy-related myeloid neoplasms

Project description:Therapy-related myeloid neoplasms (t-MNs) comprise therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndrome (t-MDS), and are a late complication of cytotoxic therapy — chemotherapy and/or radiation therapy — used in the treatment of both malignant and non-malignant diseases. The genetic profile of t-MN is markedly skewed towards high-risk cytogenetic and molecular abnormalities, and complex karyotypes with a del(5q), and TP53 mutation/loss are profoundly over-represented in t-MN as compared with de novo counterparts. To model this genetic subset, we showed that concurrent haploinsufficient expression of the del(5q) tumor suppressor genes, early growth response 1 (EGR1) and adenomatous polyposis coli (APC), cooperate with TP53 (p53) loss to induce myeloid leukemia in mice. The frequency of disease increased upon exposure to the alkylating agent, N-ethyl-N-nitrosurea (ENU) . In the context of alkylating agent therapy, cell intrinsic loss of the Egr1 and Apc del(5q) genes was sufficient to promote the development of MDS, but concurrent loss of Trp53 (p53) was required to drive AML development. We examined RNA expression in 1) LSK (Lin-, Sca1+, Kit+) hematopoietic stem and progenitor cells isolated from mice with Trp53 knockdown or without, prior to myeloid disease development, 2) bone marrow cells isolated from mice with MDS (no Trp53 knockdown) or AML (Trp53 knockdown), and 3) early passage mesenchymal stromal cells isolated from mice injected i.p. with 10% ethanol (mock) or ENU (100 mg/kg).

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Copy number analysis in de novo and therapy-related myeloproliferative neoplasms

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.

2012-11-24 | GSE42482 | GEO

Copy number analysis in de novo and therapy-related myeloproliferative neoplasms

2012-11-24 | E-GEOD-42482 | biostudies-arrayexpress

Homo sapiens

Project description:Knockdown of Hnrnpa0, a del(5q) Gene, Alters Myeloid Cell Fate in Murine Cells through Regulation of AU-rich Transcripts

| PRJNA172212 | ENA

Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) Myelodysplastic Syndromes and impact of lenalidomide

Project description:While del(5q) MDS patients comprise a well-defined hematological subgroup, the molecular basis underlying its origin and the reason behind the relapse to lenalidomide remains unknown. Using scRNAseq on CD34+ progenitor cells from patients with del(5q) MDS we were able to identify cells harboring the deletion, enabling us to deeply characterize the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. We found, across all patients, an enrichment of del(5q) cells in GMP and megakaryocyte-erythroid progenitors not described to date. Interestingly, both del(5q) and non-del(5q) cells presented similar transcriptional lesions when compared to progenitors from healthy individuals, indicating that all cells, and not only those harboring the deletion, are altered in these patients and may contribute to aberrant hematopoietic differentiation. However, GRN analysis revealed a group of regulons with aberrant activity in del(5q) cells that could be responsible for triggering altered hematopoiesis, pointing to a more prominent role of these cells in the phenotype of these patients. An analysis of del(5q) MDS patients achieving hematological response upon lenalidomide treatment showed that the drug reverted several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remained, which may be responsible for potential future relapses. Moreover, lack of hematological response was associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study provides a deep characterization of del(5q) and non-del(5q) cells at single-cell resolution, revealing previously unknown transcriptional alterations that could contribute to disease pathogenesis, or lack of responsiveness to lenalidomide.

2024-04-18 | GSE245452 | GEO

Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-κB gene network

Project description:Chromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF-κΒ activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-κB-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-κB signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-κB to sustain TRAF6/NF-κB signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML.

2014-08-23 | GSE60649 | GEO

Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor/TRAF6 signaling

Project description:TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) Myelodysplastic syndrome (MDS). Hematopoietic-specific deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cells (HSPC) proportions, altered myeloid differentiation, and progressive cytopenia. A subset of mice transplanted with Tifab knockout (KO) hematopoietic cells develop a bone marrow failure (BMF)-like disease with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPC are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic HSPC defect. Gene expression analysis of Tifab KO HSPC identified dysregulation of immune-related signatures, and hypersensitivity to Toll-like receptor 4 (TLR4) stimulation. TIFAB also forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling in HSPC, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction in vivo. Re-expression of TIFAB in human del(5q) leukemic cells results in attenuated TLR4 signaling and reduced cell viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPC by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML.

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EGR1 CHIP and RNA sequencing following EGR1 knockdown in CD34+ human hematopoeitic stem and progenitor cells

Project description:Therapy-related myeloid neoplasms (t-MN) share many similarities with AML de novo in the elderly. One common factor is that they arise in the setting of chronic inflammation, likely due to advanced age or chemotherapy-induced senescence. Here, we examined the impact of haploinsufficient loss of the del(5q) tumor suppressor gene, EGR1, commonly deleted in high-risk MNs. In mice, under the exogenous inflammatory stress of either serial transplant or successive doses of the alkylating agent ENU, Egr1-haploinsufficient hematopoietic stem cells (HSCs) exhibit a clonal advantage. Complete loss of EGR1 function is incompatible with transformation; mutations of EGR1 are rare and are not observed in the remaining allele in del(5q) patients and complete knockout of Egr1 in mice leads to HSC exhaustion. Using chromatin immunoprecipitation sequencing (ChIP-seq), we identify EGR1 binding sites in human CD34+ cord blood-derived stem and progenitor cells (HSPCs) and show that EGR1 binds genes critical for stem cell differentiation, inflammatory signaling, and the DNA damage response. Notably, in the chromosome 5 sequences frequently deleted in patients, there is a significant enrichment of innate and inflammatory genes, which may confer a fitness advantage in an inflammatory environment. Short hairpin RNA (shRNA) mediated silencing of EGR1 biases HSPCs towards a self-renewal transcriptional signature. In the absence of EGR1, cells upregulate MYC-driven proliferative signals, downregulate CDKN1A (p21), disrupt the DNA damage response, and downregulate inflammation - adaptations anticipated to confer a relative fitness advantage for stem cells especially in an environment of chronic inflammation.

2022-09-01 | GSE184931 | GEO

Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-M-NM-:B gene network

Project description:Chromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF-M-NM-:M-NM-^R activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-M-NM-:B-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-M-NM-:B signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-M-NM-:B to sustain TRAF6/NF-M-NM-:B signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML. Four del(5q) MDS/AML patients with low miR-146a expression (5284, 8839, 8285, 4233) and 5 with high miR-146a expression (7957, 5534, 4688, 4982, 8412) were selected for microarray assay. RNA was reverse transcribed and labeled, and hybridized onto the GeneChip Human Gene 1.0 ST Array. A total of nine samples were included, and two groups are assigned based on miR-146a expression. Comparison comprises mRNA expression profile of low miR-146a group v.s. high miR-146a group.

2014-08-23 | E-GEOD-60649 | biostudies-arrayexpress

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