Unknown,Transcriptomics,Genomics,Proteomics

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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 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).

ORGANISM(S): Homo sapiens

SUBMITTER: Stefan Heinrichs

PROVIDER: E-GEOD-43400 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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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Project description:Myelodysplastic syndromes (MDS) are a group of clonal hematological disorders characterized by ineffective hematopoiesis with morphological evidence of marrow cell dysplasia resulting in peripheral blood cytopenia. Microarray technology has permitted a refined high-throughput mapping of the transcriptional activity in the human genome. Noncoding-RNAs (ncRNAs) transcribed from intronic regions of genes are involved in a number of processes related to post-transcriptional control of gene expression, and in the regulation of exon-skipping and intron retention. Characterization of ncRNAs in progenitor cells and stromal cells of MDS patients could be strategic for understanding gene expression regulation in this disease. In this study, gene expression profiles of CD34+ and stromal cells of MDS patients with refractory anemia with ringed sideroblasts (RARS) subgroup were compared those of healthy individuals, using 44k combined intron-exon oligoarrays, which included probes for protein-coding genes, for sense and antisense strands of totally intronic noncoding (TIN) and for partially intronic noncoding (PIN) RNAs. In CD34+ cells of MDS-RARS patients, 217 genes were significantly differentially expressed (q-value < 0.01) in comparison to healthy individuals, of which 68 (31%) were noncoding transcripts. In stromal cells of MDS-RARS, 13 genes were significantly differentially expressed (q-value < 0.05) in comparison to healthy individuals, of which 4 (30%) were noncoding transcripts. These results demonstrated, for the first time, in CD34+ cells and stromal cells the differential ncRNA expression profile between MDS-RARS and healthy individuals, suggesting that ncRNAs may play an important role during the development of myelodysplastic syndromes. Bone marrow (BM) CD34+ cell samples were collected from 4 healthy subjects and from 4 MDS patients. Stromal samples were collected from 4 healthy subjects and 3 MDS patients. All patients were diagnosed as RARS according to the French-American-British (FAB) classification and did not present chromosomal abnormalities; they received no growth factors or any further MDS treatment.

Dataset Information

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

Publications

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

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