The transcription factor PlagL2 activates Mpl transcription and signaling in hematopoietic progenitor and leukemia cells
Program in Gene Function and Expression; Department of Microbiology and Physiologic Systems
Leukemia, Myeloid, Acute; DNA-Binding Proteins; Transcription Factors; RNA-Binding Proteins; Receptors, Thrombopoietin; Oncogene Proteins, Fusion; Core Binding Factor beta Subunit; Gene Expression Regulation
Genetics and Genomics
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 Cbfbeta-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 Cbfbeta-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 CBFbeta-SMMHC in mice.
DOI of Published Version
Leukemia. 2011 Apr;25(4):655-62. Epub 2011 Jan 25. Link to article on publisher's site
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Landrette, Sean F.; Madera, Dmitri; He, Feng; and Castilla, Lucio H., "The transcription factor PlagL2 activates Mpl transcription and signaling in hematopoietic progenitor and leukemia cells" (2011). Program in Gene Function and Expression Publications and Presentations. 150.