Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Loss of BTG1 function promotes ETV6-RUNX1-mediated leukemic transformation by upregulation of BCL6

ABSTRACT: Analysis of gene signatures in WT+Ctrl vs WT+ETV6-RUNX1, Btg1-/- and Btg1-/-+ETV6-RUNX1 in cKit+Ter119- fetal liver-derived hematopoietic progenitor cells (FL-HPCs). The Btg1-/-+ETV6-RUNX1 FL-HPCs display a strong increase in proliferation compared to WT+ETV6-RUNX1. Total RNA otained from WT+Ctrl, WT+ETV6-RUNX1, Btg1-/-+Ctrl and Btg1-/-+ETV6-RUNX1 FL-HPCs cells that were cultured for 12 days in expansion medium.

ORGANISM(S): Mus musculus

SUBMITTER: Frank van Leeuwen

PROVIDER: E-GEOD-60589 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The RUNX genes encode for transcription factors involved in development and human disease. RUNX1 and RUNX3 are frequently associated with leukemias, yet the basis for their involvement in leukemogenesis is not fully understood. Here we show that Runx1;Runx3 double knockout (DKO) mice exhibited lethal phenotypes due to bone marrow failure and myeloproliferative disorder. These contradictory clinical manifestations are reminiscent of human inherited bone marrow failure syndromes like Fanconi anemia (FA), caused by defective DNA repair. Indeed, Runx1;Runx3 DKO cells showed mitomycin C hypersensitivity, due to impairment of monoubiquitinated-FANCD2 recruitment to DNA damage foci, although FANCD2 monoubiquitination in the FA pathway was unaffected. RUNX1 and RUNX3 interact with FANCD2 independent of CBFM-NM-2, suggesting non-transcriptional role for RUNX in DNA repair. These findings suggest that RUNX dysfunction causes DNA repair defect, besides transcriptional misregulation, and promotes development of leukemias and other cancers. 6 mice were analyzed in this study. 3 Runx1;Runx3 double knockout cKit+Sca1+Lin- hematopoietic stem/progenitor cells were compared with their wild type littermate controls. RNA was isolated from 3 independent Runx1;Runx3 WT KSL samples, each pooled from 3 Runx1;Runx3 WT mice, and 3 independent Runx1;Runx3 DKO KSL samples, using the RNeasy Micro Kit (QIAgen). RNA integrity and quantity was assessed using the Agilent 2000 Bioanalyzer system. 3 M-NM-<g to 5 M-NM-<g RNA was processed using WT-Ovation Pico RNA Amplification System (NuGEN) paired with the WT-Ovation Exon Module and FL-Ovation cDNA Biotin Module (NuGEN). A detailed protocol in the userM-bM-^@M-^Ys guide kit was used without modification. cDNA were prepared for hybridization on GeneChip Mouse Gene 1.0 ST Arrays (Affymetrix) according to the instructions in GeneChip Hybridization Wash and Stain Kit for ST arrays (Affymetrix). Microarray hybridization, scanning and preliminary MAS 5.0 normalizations were completed at the A*STAR Biopolis Shared Facilities (BSF).

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Loss of BTG1 function promotes ETV6-RUNX1-mediated leukemic transformation by upregulation of BCL6

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