Transcript Map and Comparative Analysis of the 1.5-Mb Commonly Deleted Segment of Human 5q31 in Malignant Myeloid Diseases with a del(5q)

Lai, Fang; Godley, Lucy A.; Joslin, John M.; Fernald, Anthony A.; Liu, Jin; Espinosa, Rafael; Zhao, Nan; Pamintuan, Leslie; Till, Brian G.; Larson, Richard A.; Qian, Zhijian; Beau, Michelle M. Le

doi:10.1006/geno.2000.6414

Cited by 88 publications

(64 citation statements)

References 42 publications

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“…Several groups have delineated a CDR on chromosome 5, but a gene contributing to these disorders in this region has yet to be identified. 15,24,35 As a-catenin was on our list of 39 genes, we decided to characterize the methylation and expression status of a-catenin in 5q-MDS and AML samples. Given the lack of a good 5q-cell model system, myeloid leukemia cell models systems were used.…”

Section: Discussionmentioning

confidence: 99%

“…14 Approximately 10% of de novo AML and MDS patients present with a 5q deletion. 15,16 Here, we identify a gene located within common deleted regions (CDRs) of 5q31, a-catenin (CTNNA1), whose expression is induced by DAC and SAHA treatment in myeloid cell lines. Further analysis of the expression level of a-catenin in a panel of patients with either a 5q-AML or MDS showed that this gene was significantly decreased in expression when compared to non-5q-AML/MDS samples.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of epigenetically silenced genes in acute myeloid leukemias

Raynaud

Tung

et al. 2007

Leukemia

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The demethylating 5-aza-2 0 deoxycytidine (DAC) and the histone deacetylase inhibitor (HDACi) suberoyl anilide bishydroxamide (SAHA) possess potent antitumorigenic properties in myeloid disorders. However, the transcriptome alterations mediated by these drugs are poorly understood. We analyzed the transcriptional effects of DAC and SAHA in the AML cell line KG-1. Microarray analyses revealed 76 genes expressed in normal CD34 þ cells, absent in KG-1 cells but whose expression was induced after drug treatment. A total of 39 of these genes harbored CpG islands in their promoters. We examined the expression level of these genes in 120 AML patient samples representing diverse karyotpyes. Gas2l1, tfIIs, ehd3, enolase 2, mx1, dral, astml and pxdn were diminished across all AML karyotypes examined. Ehd3 was methylated in 63% of AML patients examined. This methylation was lost upon complete remission, and not observed in normal CD34 þ cells. CD34 þ cells expressed ehd3 at approximately 10-fold higher levels than AML samples. Another highlighted gene, a-catenin, is located at q31 of chromosome 5. Analyses of 29 5q-AML/ myelodysplastic syndrome (MDS) samples revealed marked decreases in expression of a-catenin, compared to non-5q-MDS samples (6.679-fold). However, no methylation was detected, suggesting indirect effects of these drugs on the expression of a-catenin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of epigenetically silenced genes in acute myeloid leukemias

Raynaud

Tung

et al. 2007

Leukemia

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“…[3][4][5] Previously, we defined a 970 kb commonly deleted segment (CDS) at 5q31.2 that is lost in all t-MN and acute myeloid leukemia (AML) de novo patients with abnormalities of chromosome 5. 6 This region contains 19 genes and 1 micro-RNA sequence; however, none of the genes revealed inactivating mutations or silencing by DNA methylation of the remaining allele. 6,7 For this reason, we advanced the hypothesis that AML with a del(5q) results from haploinsufficiency of one or more genes on 5q.…”

Section: Introductionmentioning

confidence: 99%

“…6 This region contains 19 genes and 1 micro-RNA sequence; however, none of the genes revealed inactivating mutations or silencing by DNA methylation of the remaining allele. 6,7 For this reason, we advanced the hypothesis that AML with a del(5q) results from haploinsufficiency of one or more genes on 5q. One del(5q) candidate of interest is the heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0) gene encoding a RNA-binding protein that binds to adenylate-uridylate (AU)-rich elements (AREs) and is believed to be a positive regulator of transcript stability.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o nhave a profound impact upon hematopoiesis, and consequently contribute to the changes seen in t-MN patients.In this study, we now add HNRNPA0 to the growing list of AUBPs that are recognized for their vital roles in hematopoiesis and leukemogenesis. Herein, we show that HNRNPA0 is highly expressed in hematopoietic stem cells, and its expression exhibits dynamic changes during the course of differentiation. Deletion of a single allele of HNRNPA0 is associated with haploinsufficient transcript levels in CD34 + cells from t-MN patients with a del(5q). Modeling HNRNPA0 haploinsufficiency in mouse cells alters myeloid lineage fate, in part through changes in the expression of ARE-containing genes, suggesting that a decreased dose of HNRNPA0 in t-MN patients may contribute to leukemogenesis. Moreover, we determined that ARE mRNAs in t-MN patients with a del(5q) are enriched in transcripts that encode proteins associated with increased growth and proliferation. Methods Retroviral transduction and in vitro differentiation of PUER and primary mouse hematopoietic cellsA short interfering RNA hairpin (shRNA), designed to match bases 288 to 306 of the open reading frame of Hnrnpa0 with a 9 nucleotide loop in the center, or a scrambled, irrelevant sequence, 17 was cloned into pBanshee-GFP (an MSCV-based construct with P CMV -driven GFP). The PUER cell line or mouse bone marrow cells from BALB/cAnNTac mice (Taconic, Hudson, NY, USA) were transduced by spinoculation with viral supernatants from HEK-293T cells co-transfected with the shRNA-containing pBanshee and pCL-ECO packaging plasmids (Imgenex, San Diego, CA, USA) using Effectene (Qiagen, Germantown, MD, USA). Two days post infection, the cells were sorted on a FACSAria (BD Biosciences, San Jose, CA, USA) for GFP positivity. All animal studies were approved by the University of Chicago Institutional Animal Care and Use Committee and mice were housed in a fully-AALAC-accredited facility. GFP + sorted PUER cells, expressing the Hnrnpa0 or control shRNA, were expanded in IL-3 for four days and then treated with 1-5 nM 4-hydroxytamoxifen (4-OHT, >98% (TLC) Z-isomer, Sigma, St. Louis, MO, USA) to induce macrophage differentiation. For gene expression, flow cytometry and morphological analyses, cells were sampled at 24 h, 4 days, and 7days, respectively. GFP + bone marrow cells were plated in MethoCult GF M3434 (StemCell Technologies, Vancouver, BC, Canada). After 12 days of incubation, colonies of greater than 50 cells were scored for morphology by inverted light microscopy. Cells were then collected and stained with Mac-1 (CD11b) antibodies in combination with either F4/80 or Gr-1 (Ly-6G) antibodies, and analyzed on a FASCanto benchtop flow cytometric analyzer (BD Biosciences, San Jose, CA, USA). Patient samplesAll 38 t-MNs used for gene expression profiling analysis were obtained from patients treated with chemotherapy and/or radiation therapy at the University of Chicago who were diagnosed with t-MN between January 1984...

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“…4,5 The 1-1.5-Mb CDR at 5q31 identified in AML and the more advanced forms of MDS by Lai and coworkers 74 is distinct from the CDR of the 5qϪ syndrome. This more proximal CDR is essentially defined by small numbers of patients with atypical 5q deletions, although a large group of patients with the del(5q) was studied in total.…”

Section: Relationship Of 5q؊ Syndrome To Other Leukemiasmentioning

confidence: 99%

Advances in the 5q− syndrome

Boultwood

Pellagatti

McKenzie

et al. 2010

Blood

110

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The 5q؊ syndrome is the most distinct of all the myelodysplastic syndromes with a clear genotype/phenotype relationship. The significant progress made during recent years has been based on the determination of the commonly deleted region and the demonstration of haploinsufficiency for the ribosomal gene RPS14. The functional screening of all the genes in the commonly deleted region determined that RPS14 haploinsufficiency is the probable cause of the erythroid defect in the 5q؊ syndrome. A mouse model of the human 5q؊ syndrome has now been created by chromosomal engineering involving a large-scale deletion of the Cd74-Nid67 interval (containing RPS14). A variety of lines of evidence support the model of ribosomal deficiency causing p53 activation and defective erythropoiesis, including most notably the crossing of the "5q؊ mice" with p53-deficient mice, thereby ameliorating the erythroid progenitor defect. Emerging evidence supports the notion that the p53 activation observed in the mouse model may also apply to the human 5q؊ syndrome. Other mouse modeling data suggest that haploinsufficiency of the microRNA genes miR-145 and miR-146a may contribute to the thrombocytosis seen in the 5q؊ syndrome. Lenalidomide has become an established therapy for the 5q؊ syndrome, although its precise mode of action remains uncertain. (Blood. 2010;116(26): 5803-5811) IntroductionThe 5qϪ syndrome was first described by Van den Berghe et al in 1974. 1 The well-known clinical features of the 5qϪ syndrome described in the first report are macrocytosis, anemia, a normal or high platelet count, and hypolobulated megakaryocytes in the bone marrow. Over the years, a female preponderance and a good prognosis with approximately 10% of patients transforming to acute myeloid leukemia (AML) have been well documented. [2][3][4][5] The World Health Organization classification of myelodysplastic syndromes (MDSs) recognizes the 5qϪ syndrome as a distinct entity defined by a medullary blast count of less than 5% and the deletion of 5q [del(5q)] as the sole karyotypic abnormality. 6 It should be noted that patients not correctly defined as 5qϪ syndrome (ie, with either additional karyotypic abnormalities or excess blasts) do not have a good prognosis. 7 The majority of patients with the 5qϪ syndrome become transfusion dependent over time with the potential for iron loading. 5,8 A recent paper by Patnaik et al 2 determined that age, transfusion need at diagnosis, and dysgranulopoiesis were independent predictors of shortened survival in patients with the 5qϪ syndrome tightly defined according to World Health Organization criteria.One of the features that first stimulated research on the 5qϪ syndrome was the localization of many genes relevant to hematopoiesis to the long arm of chromosome 5 (5q). 4 The gene cluster at 5q31 includes interleukins 3, 4, 5, 9, 13, and 17␤ and granulocytemonocyte colony stimulating factor. 9 Several cytokine receptor genes are located on 5q, including colony-stimulating factor 1 receptor and platelet-derived growth fa...

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Transcript Map and Comparative Analysis of the 1.5-Mb Commonly Deleted Segment of Human 5q31 in Malignant Myeloid Diseases with a del(5q)

Cited by 88 publications

References 42 publications

Discovery of epigenetically silenced genes in acute myeloid leukemias

Discovery of epigenetically silenced genes in acute myeloid leukemias

Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts

Advances in the 5q− syndrome

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