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MYBL2 Is a Sub-haploinsufficient Tumor Suppressor Gene in Myeloid Malignancy

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Stefan Heinrichs

PROVIDER: E-GEOD-43401 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.

Heinrichs Stefan S Conover Lillian F LF Bueso-Ramos Carlos E CE Kilpivaara Outi O Stevenson Kristen K Neuberg Donna D Loh Mignon L ML Wu Wen-Shu WS Rodig Scott J SJ Garcia-Manero Guillermo G Kantarjian Hagop M HM Look A Thomas AT

eLife 20130716

A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipot ...[more]

PMID: 23878725

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MYBL2 Is a Sub-haploinsufficient Tumor Suppressor Gene in Myeloid Malignancy (RNAi)

Project description:A dosage-dependent role for tumor suppressor genes in the initiation of myeloid malignancies remains controversial. Here we show that MYBL2 is expressed at sharply reduced levels in CD34+ cells from most patients with myelodysplastic syndrome (MDS; 65%; n=26). In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors led to clonal dominance by these M-bM-^@M-^\sub-haploinsufficientM-bM-^@M-^] cells, affecting all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. Thus, downregulation of MYBL2 activity to levels below those predicted by classical haploinsufficiency drives the clonal expansion of hematopoietic progenitors in a large fraction of human MDS cases. Cryopreserved CD34+ bone marrow were cultured for 24 hours, transduced with shRNA-encoding vectors and selected with Puromycin for 48 hours. Vectors shRNA 1-8 are specifically targeting MYBL2, vectors shRNA A-D encoded an irrelevant control shRNAs and one culture was left untreated (no shRNA). Cells were harvested after Puromycin selection and total RNA was prepared using Trizol (LifeTechnologies).

2013-09-15 | E-GEOD-43400 | biostudies-arrayexpress

MYBL2 Is a Sub-haploinsufficient Tumor Suppressor Gene in Myeloid Malignancy (RNA)

Project description:A dosage-dependent role for tumor suppressor genes in the initiation of myeloid malignancies remains controversial. Here we show that MYBL2 is expressed at sharply reduced levels in CD34+ cells from most patients with myelodysplastic syndrome (MDS; 65%; n=26). In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors led to clonal dominance by these M-bM-^@M-^\sub-haploinsufficientM-bM-^@M-^] cells, affecting all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. Thus, downregulation of MYBL2 activity to levels below those predicted by classical haploinsufficiency drives the clonal expansion of hematopoietic progenitors in a large fraction of human MDS cases. Total RNA was prepared from CD34+ bone marrow cells obtained from MDS patients or healthy controls.

2013-09-15 | E-GEOD-43399 | biostudies-arrayexpress

Comparison of Ly6D- common lymphoid progenitors (CLPs) from OcnCre;iDTR control and mutant mice.

Project description:We performed gene expression microarray comparing Ly6D- CLPs isolated from OcnCre;iDTR control and mutant mice by flow cytometry. Ly6D- CLPs were isolated from the bone marrow of OcnCre;iDTR control or mutant mice by flow cytometry and subjected to Affymetrix microarray comparison of gene expression. Markers used to define Ly6D- CLP by flow cytometry was: LineageLo, cKit+, Sca+, CD127+, Thy1.2-, Ly6D-

2015-04-10 | E-GEOD-66102 | biostudies-arrayexpress

Gene expression in diploid and evolved tetraploid RPE-1 and BJ-1 cells

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2014-05-22 | E-GEOD-57864 | biostudies-arrayexpress

Murine bone marrow gene expression profiling

Project description:Mice have been treated with olaptesed pegol (NOX-A12). Whole BM cells have been harvested, RNA isolated, and gene expression profiling was performed on cDNA using Mouse Genome 430 2.0 array. Untreated mice have been used as control. Mice have been treated with NOX-A12. Whole BM cells have been harvested, RNA isolated, and gene expression profiling was performed on cDNA using Mouse Genome 430 2.0 array. Untreated mice have been used as control.

2015-05-18 | E-GEOD-42257 | biostudies-arrayexpress

Comparison of Osx+ cells and Ocn+ cells in the bone marrow.

Project description:We performed gene expression microarray comparing Osx-mCherry cells and Ocn-Topaz cells isolated from the OsxCre-mCherry;OcnCre-Topaz double transgenic mice by flow cytometry. In the OsxCre-mCherry;OcnCre-Topaz mouse model, Osx+ cells were labeled red, Ocn+ cells were green, and Osx+Ocn+ cells were yellow within the same animal. This system allows isolation of osteolineage subsets within the same animal by flow cytometry.

2015-04-10 | E-GEOD-66042 | biostudies-arrayexpress

Transcription profiling of mouse multiple myeloma tumors and splenic B cells from transgenics overexpressing XBP-1s

Project description:Multiple myeloma (MM) evolves from highly prevalent premalignant condition termed Monoclonal Gammopathy of Undetermined Significance (MGUS). We report an MGUS-MM phenotype arising in transgenic mice with Emu-directed expression of the unfolded protein/ER stress response and plasma cell development spliced isoform factor XBP-1s. Emu-XBP-1s elicited elevated serum Ig and IL-6 levels, skin alterations and with advancing age, a significant proportion of Emu-xbp-1s transgenic mice develop features diagnostic of human MM including bone lytic lesions. Transcriptional profiles of Emu-xbp-1s B lymphoid and MM cells show aberrant expression of genes known to be dysregulated in human MM including Cyclin D1, MAF, MAFB, and APRIL. This genetic model coupled with documented frequent XBP-1s overexpression in human MM serve to implicate chronic XBP-1s dysregulation in the development of this common and lethal malignancy. Experiment Overall Design: In this study, we have explored the biological impact of sustained XBP-1s expression in the lymphoid system, anticipating that this genetic event would be a necessary component along with other MM-relevant oncogenes and tumor suppressor gene manipulations to generate a MM-prone mouse model. Unexpectedly, XBP-1s overexpression alone yielded an MGUS-MM disease bearing many features classical of the human disease on the clinical, pathological and molecular levels. Experiment Overall Design: We performed expression analysis of B cells derived from the spleen of 20-week old Emu-xbp-1s mice (n=5) and non-transgenic mice (n=5). Additionally, we analyzed the expression profiles from MM tumor cells arising in Emu-xbp-1s mice (n=6).

2007-11-06 | E-GEOD-6980 | biostudies-arrayexpress

Culture-expanded mouse lymph node-derived fibroblastic reticular cells

Project description:Lymph node stromal cells were isolated from young C57Bl6/J mice and ex-vivo expanded and purified for gene expression analysis. The aim was to assess gene expression patterns for cultured FRCs. Two replicate samples of untreated young (4-6 weeks old) C57BL6/J mice

2014-08-14 | E-GEOD-60111 | biostudies-arrayexpress

Gene expression data from cultured mouse cortical (mCTX) neurons in different stimulation and knockdown conditions

Project description:Although the induction of C-FOS in the brain has been extensively studied for several decades to date there has been no attempt to identify the targets of C-FOS at a genome wide level, and it was not known how many genes C-FOS activates in a given cell. To identify potential C-FOS target genes, we performed microarray analysis on RNA obtained from mouse cortical (mCTX) neurons infected with lentivirus containing either a control shRNA (targeting firefly luciferase) or c-Fos shRNA that were subsequently depolarized with 0, 1, 3, or 6 hours of KCl. Embryonic day 16.5 cortices from C57BL/6 mice were dissected, dissociated, plated, and subsequently grown in a cell culture incubator that maintained a temperature of 37 degrees C and a CO2 concentration of 5%. On DIV5, lentiviral supernatant containing either a lentivirus expressing a control shRNA targeting firefly luciferase or a lentivirus expressing shRNA targeting c-Fos was applied to cultures for 6hrs with 6ug/mL polybrene. At DIV7, mCTX neurons were silenced and stimulated with KCl for either 0, 1, 3, or 6hrs, and total RNA was purified using Trizol and the RNeasy mini kit from Qiagen. 10ug of labeled cDNA was subsequently hybridized to Affymetrix mouse genome 430 2.0 arrays with affymetrix processing.

2014-09-07 | E-GEOD-60049 | biostudies-arrayexpress

Probing off-target effect of LMNA siRNA and pro-siRNA in HeLa-d1EGFP cell line

Project description:We have develped a novel method of making siRNAs (named pro-siRNA for prokaryotic siRNA). To evaluate off-targeting of pro-siRNA, we compared mRNA expression profile of HeLa-d1EGFP cells transfected with 4 nM LMNA siRNAs and pro-siRNAs by microarray. We used microarray to study off-target effect of siRNAs in HeLa-d1EGFP cell line. After transfection of siRNAs for 24 hrs, RNA were extracted using Trizol. RNA samples were sent to Microarray Core at Dana-Farber Cancer Institute (http://macf-web.dfci.harvard.edu/index.php?option=com_frontpage&Itemid=1) to be probed using Human Gene 1.0 ST (Affymetrix).

2013-02-06 | E-GEOD-44105 | biostudies-arrayexpress

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