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

ABSTRACT: 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 “sub-haploinsufficient” 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43400 | GEO | 2013/09/15

SECONDARY ACCESSION(S): PRJNA185831

REPOSITORIES: GEO

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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

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)

2013-09-15 | GSE43399 | GEO

Transcriptional profiling of bone marrow cells of MDS patients

2009-05-28 | GSE16236 | GEO

Transcriptional profiling of bone marrow cells of MDS patients

Project description:Myelodysplastic Syndromes (MDSs) are a heterogeneous family of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis and frequently leukemia progression. To exlore how MDS develop into leukemia, we performed the transcriptional profiling of lesional cells and normal lymphoid cells from the MDS patients. Bone marrow cells from the MDS patients were sorted into blastic, myeloid, erythroid and lymphoid fractions by flow cytometry and then were profiled transcriptionally by Human Human Genome U133 Plus 2.0 arrays. Differentially expressed genes between lesional cells and lymphoid cells were identified by SAM.

2009-05-28 | E-GEOD-16236 | biostudies-arrayexpress

Oxidative stress in myelodysplastic syndromes

Project description:Control of oxidative stress in the bone marrow (BM) is key for maintaining the balance between self-renewal, proliferation, and differentiation of hematopoietic cells. Breakdown of this regulation can lead to diseases characterized by BM failure such as the myelodysplastic syndromes (MDS). To better understand the role of oxidative stress in MDS development, we compared protein carbonylation as an oxidative stress marker in BM of patients with MDS and control subjects, and also patients with MDS under treatment with the iron chelator deferasirox.

2019-10-30 | PXD013609 | Pride

Gene expression profiling of myelodysplastic CD34+ hematopoietic stem cells treated in vitro with decitabine

Project description:Epigenetic mechanisms contribute to deregulated gene expression of hematopoietic progenitors in Myelodysplastic Syndromes (MDS). Hypomethylating agents are able to improve peripheral cytopenias in MDS patients. To identify critical gene expression changes induced by hypomethylating agents, we analyzed gene expression profiling (GEP) of myelodysplastic and normal CD34+ hematopoietic stem cells treated in vitro with or without decitabine. Four MDS and two untreated early stage Hodgkin’s lymphomas were analyzed for GEP. Mock treated CD34+ stem cells segregate according to diagnosis and karyotype. After decitabine treatment, gene expression changes were more consistent on MDS CD34+ cells with abnormal kayotype. Comparing decitabine-induced genes with those found down-regulated in mock-treated MDS cells, we identified a list of candidate tumor suppressor genes in MDS. By real-time RT-PCR we confirmed expression changes for three selected genes CD9, CXCR4 and GATA2 in 12 MDS patients and 4 controls. CD9 was widely repressed in most MDS CD34+ cell samples, although similar levels of methylation were found in both normal and MDS total bone marrows. CXCR4 promoter methylation was absent in total bone marrows from 36 MDS patients. In conclusion, changes in gene expression changes induced by hypomethylating treatment are more pronounced in CD34+ cells from abnormal karyotype.

2009-12-23 | GSE19610 | GEO

Genistein Protects Hematopoietic Stem Cells against G-CSF-Induced DNA Damage

Project description:Granulocyte colony-stimulating factor (G-CSF) has been utilized to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). SCN patients develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. MDS and AML that arise in these settings are commonly associated with chromosomal deletions. We demonstrate that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell population. Furthermore, primitive hematopoietic progenitors from G-CSFM-bM-^@M-^Streated mice show evidence of DNA damage as demonstrated by an increase in double strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein appears to be related to its preferential inhibition of G-CSFM-bM-^@M-^Sinduced proliferation of hematopoietic stem cells. Importantly, genistein does not impair G-CSFM-bM-^@M-^Sinduced proliferation of committed hematopoietic progenitors, nor diminish neutrophil production. The protective effect of genistein was accomplished with plasma levels that are easily attainable through dietary supplementation. aCGH was performed using NimbleGen DNA was extracted from bone marrow samples from mice treated with G-CSF or diluent for 4 months and analyzed using NimbleGen 3x720K mouse copy number arrays

2014-02-07 | E-GEOD-54737 | biostudies-arrayexpress

Expression data of ribosomal proteins from sorted hematopoietic stems cells from patients with low risk MDS.

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2011-08-13 | E-GEOD-30201 | biostudies-arrayexpress

Global binding profiles of MYBL2 and FOXM1 in lung adenocarcinoma reveal that MYBL2 regulates FOXM1 to control cell-cycle genes including CENPA [ChIP-seq]

Project description:MYBL2 is a transcription factor that has either pro-survival or anti-survival functions in a cell-type specific manner. Overexpression of MYBL2 is associated with worse survival of lung adenocarcinoma, but the mechanism by which it regulates transcription has not yet been elucidated. In this study, we found that MYBL2 mainly binds to the promoters of highly expressed genes in lung adenocarcinoma cells using ChIP-seq. Using knock-down and RNA-seq approach, we identified over a thousand of genes deregulated by MYBL2. By integrating ChIP-seq and RNA-seq data, we identified target genes of MYBL2. We revealed that FOXM1 is regulated by MYBL2 in lung adenocarcinoma cells, and FOXM1 binding sites are largely shared with MYBL2 binding sites. We treated lung adenocarcinoma cells with FDI-6, a known FOXM1 inhibitor and investigated the effect of FDI-6 in transcriptional regulation of MYBL2 and FOXM1. We found that CENPA is one of the key genes regulated by MYBL2 and FOXM1, and that it can be inhibited by FDI-6. Our signaling pathway analysis results revealed that MYBL2 and FOXM1 activate cell-cycle genes, suggesting that MYBL2 and FOXM1 act as oncogenic transcription factors in lung adenocarcinoma cells and FDI-6 could be a potential treatment of the disease.

2022-11-02 | GSE201271 | GEO

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