Bortezomib Induces Granulocytic Differentiation of CD34 Cells from Congenital Neutropenia Patients by Reversing Hyperactivate-STAT5a- Dependent Downregulation of LEF-1
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چکیده
The transcription factor LEF-1 (lymphoid enhancer-binding factor 1), which plays a definitive role in granulocyte colony-stimulating factor receptor (G-CSFR)-triggered granulopoiesis, is downregulated in granulocytic progenitors of severe congenital neutropenia (CN) patients. However, the exact mechanism of LEF-1 downregulation is unclear. CN patients are responsive to therapeutically high doses of G-CSF and are at increased risk of developing acute myeloid leukemia (AML). The normal expression of LEF-1 in monocytes and lymphocytes, whose differentiation is unaffected in CN, suggests the presence of a granulopoiesis-specific mechanism downstream of G-CSF receptor signaling that leads to LEF-1 downregulation. STAT5 (signal transducer and activator of transcription 5) is activated by G-CSF and is hyperactivated in AML. Here, we investigated the effects of activated STAT5 on LEF-1 expression and functions in hematopoietic progenitor cells. We demonstrated that constitutively active STAT5a (caSTAT5a) inhibited LEF-1-dependent autoregulation of the LEF-1 gene promoter by binding to the LEF-1 protein, recruiting NLK (Nemo-like kinase) and the E3 ubiquitinligase NARF to LEF-1, leading to LEF-1 ubiquitination and a reduction in LEF-1 protein levels. The proteasome inhibitor bortezomib reversed the defective G-CSF-triggered For personal use only. on October 31, 2017. by guest www.bloodjournal.org From
منابع مشابه
Bortezomib inhibits STAT5-dependent degradation of LEF-1, inducing granulocytic differentiation in congenital neutropenia CD34(+) cells.
The transcription factor lymphoid enhancer-binding factor 1 (LEF-1), which plays a definitive role in granulocyte colony-stimulating factor (G-CSF) receptor-triggered granulopoiesis, is downregulated in granulocytic progenitors of severe congenital neutropenia (CN) patients. However, the exact mechanism of LEF-1 downregulation is unclear. CN patients are responsive to therapeutically high doses...
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تاریخ انتشار 2014