The Leukemia-associated Fusion Protein Tel-Platelet-derived Growth Factor Receptor β (Tel-PdgfRβ) Inhibits Transcriptional Repression of PTPN13 Gene by Interferon Consensus Sequence Binding Protein (Icsbp)

摘要

Icsbp is an interferon regulatory transcription factor with leukemia suppressor activity. In previous studies, we identified the gene encoding Fas-associated phosphatase 1 (Fap1; the PTPN13 gene) as an Icsbp target. In the current study, we determine that repression of PTPN13 by Icsbp requires cooperation with Tel and histone deacetylase 3 (Hdac3). These factors form a multiprotein complex that requires pre-binding of Tel to the PTPN13 cis element with subsequent recruitment of Icsbp and Hdac3. We found that knockdown of Tel or Hdac3 in myeloid cells increases Fap1 expression and results in Fap1-dependent resistance to Fas-induced apoptosis. The TEL gene was initially identified due to involvement in leukemia-associated chromosomal translocations. The first identified TEL translocation partner was the gene encoding platelet-derived growth factor receptor β (PdgfRβ). The resulting Tel-PdgfRβ fusion protein exhibits constitutive tyrosine kinase activity and influences cellular proliferation. In the current studies, we find that Tel-PdgfRβ influences apoptosis in a manner that is independent of tyrosine kinase activity. We found that Tel-PdgfRβ expressing myeloid cells have increased Fap1 expression and Fap1-dependent Fas resistance. We determined that interaction between Tel and Tel-PdgfRβ decreases Tel/Icsbp/Hdac3 binding to the PTPN13 cis element, resulting in increased transcription. Therefore, these studies identify a novel mechanism by which the Tel-PdgfRβ oncoprotein may contribute to leukemogenesis.