ABSTRACT
Cytokine signaling pathways are frequent targets of oncogenic mutations in acute myeloid leukemia (AML), promoting proliferation and survival. We have previously shown that the transcription factor PLAGL2 promotes proliferation and cooperates with the leukemia fusion protein Cbfß-SMMHC in AML development. Here, we show that PLAGL2 upregulates expression of the thrombopoietin receptor Mpl, using two consensus sites in its proximal promoter. We also show that Mpl overexpression efficiently cooperates with Cbfß-SMMHC in development of leukemia in mice. Finally, we demonstrate that PlagL2-expressing leukemic cells show hyper-activation of Jak2 and downstream STAT5, Akt and Erk1/2 pathways in response to Thpo ligand. These results show that PlagL2 expression activates expression of Mpl in hematopoietic progenitors, and that upregulation of wild-type Mpl provides an oncogenic signal in cooperation with CBFß-SMMHC in mice.
Subject(s)
DNA-Binding Proteins/physiology , Hematopoietic Stem Cells/metabolism , Leukemia, Myeloid, Acute/metabolism , RNA-Binding Proteins/physiology , Receptors, Thrombopoietin/genetics , Signal Transduction , Transcription Factors/physiology , Transcription, Genetic , Animals , Base Sequence , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Bone Marrow Transplantation , Cells, Cultured , Electrophoretic Mobility Shift Assay , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Flow Cytometry , Gene Expression Profiling , Humans , Immunoblotting , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Leukemia, Myeloid, Acute/genetics , Luciferases/metabolism , Male , Mice , Mice, Transgenic , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis , Oncogene Proteins, Fusion/physiology , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , Receptors, Thrombopoietin/metabolism , Reverse Transcriptase Polymerase Chain Reaction , STAT5 Transcription Factor/genetics , STAT5 Transcription Factor/metabolism , Sequence Homology, Nucleic Acid , TransfectionABSTRACT
The Human Genome Project stimulated the development of efficient strategies and relevant hardware for complete genome sequencing. The comparative genomic approach extends the possibilities of using the sequencing data to identify new genes or conserved regulatory regions by means of nucleotide sequence alignment of the particular regions of the mouse and human genomes, or to trace the evolutionary events resulting in the genome structure of modern mammals. The review focuses on the use of new molecular cytogenetic methods along with computer-aided analysis of the genomes in vertebrates. Several factors hindering data analysis are considered. The currently available information on gene evolution rate inferred from comparative genomic data is presented. The origin and evolution of the genomes of several species are discussed.
