Abstract
ETV6 is an ETS family transcription factor that plays a key role in hematopoiesis and megakaryocyte development. Our group and others have identified germline mutations in ETV6 resulting in autosomal dominant thrombocytopenia and predisposition to malignancy; however, molecular mechanisms defining the role of ETV6 in megakaryocyte development have not been well established. Using a combination of molecular, biochemical, and sequencing approaches in patient-derived PBMCs, we demonstrate abnormal cytoplasmic localization of ETV6 and the HDAC3/NCOR2 repressor complex that led to overexpression of HDAC3-regulated interferon response genes. This transcriptional dysregulation was also reflected in patient-derived platelet transcripts and drove aberrant proplatelet formation in megakaryocytes. Our results suggest that aberrant transcription may predispose patients with ETV6 mutations to bone marrow inflammation, dysplasia, and megakaryocyte dysfunction.
Highlights
ETV6, the E26 transformation-specific (ETS) family transcription repressor and tumor suppressor variant 6 gene, resides on chromosome 12p13 and encodes a 57 kDa ETS family transcription factor with 3 highly conserved functional domains [1, 2]: an N-terminal pointed (PNT) dimerization domain, a central linker domain, and an 85–amino acid C-terminal ETS DNA-binding domain, which associates with the 5′GGA(A/T)3′ motif in the promoter region of target genes [2]
We describe 2 ETV6 germline mutations residing in distinct domains of the protein that causes cytoplasmic mislocalization of ETV6, and of the ETV6-associated HDAC3/NCOR2 complex, altering the transcriptional profile of PBMCs and impairing MK proplatelet formation
We demonstrated that ETV6 P214L and R369Q PBMCs had upregulated proinflammatory interferon response genes, which are known to be regulated by HDAC3 [24]
Summary
ETV6, the E26 transformation-specific (ETS) family transcription repressor and tumor suppressor variant 6 gene, resides on chromosome 12p13 and encodes a 57 kDa ETS family transcription factor with 3 highly conserved functional domains [1, 2]: an N-terminal pointed (PNT) dimerization domain, a central linker domain, and an 85–amino acid C-terminal ETS DNA-binding domain, which associates with the 5′GGA(A/T)3′ motif in the promoter region of target genes [2]. While ETV6 is known to dimerize to achieve its transcriptional function, it has been reported to associate with other corepressors, such as HDAC3, NCOR, and Sin3 [9]. ETV6 is a well-studied hematopoietic transcription factor previously reported to play a key functional role in hematopoiesis, megakaryopoiesis, cell growth, and differentiation [11, 14,15,16]. Conditional knockout of Etv in megakaryocyte (MK) erythroid progenitor cells in mice results in thrombocytopenia, with an increased frequency of MK colony-forming cells [14]. These findings are consistent with a terminal defect in MK maturation, leading to a compensatory increase in MK progenitor cells.
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