Functional analysis of germlineETV6 W380Rmutation causing inherited thrombocytopenia and secondary acute lymphoblastic leukemia or essential thrombocythemia

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Authors	STAŇO KOZUBÍK Kateřina RADOVÁ Lenka RÉBLOVÁ Kamila ŠMÍDA Michal KUBRICANOVA ZALIOVA Marketa BALOUN Jiří PEŠOVÁ Michaela VRZALOVÁ Zuzana FOLBER František MEJSTŘÍKOVÁ Soňa POSPÍŠILOVÁ Šárka DOUBEK Michael
Year of publication	2021
Type	Article in Periodical
Magazine / Source	Platelets
MU Faculty or unit	Central European Institute of Technology
Citation
Web	https://www.tandfonline.com/doi/full/10.1080/09537104.2020.1802416
Doi	http://dx.doi.org/10.1080/09537104.2020.1802416
Keywords	Acute lymphoblastic leukemia; ETV6; myeloproliferative neoplasm; second hit
Description	Germline mutations inETV6gene cause inherited thrombocytopenia with leukemia predisposition. Here, we report on functional validation ofETV6W380R mutation segregating with thrombocytopenia in a family where two family members also suffered from acute lymphoblastic leukemia (ALL) or essential thrombocythemia (ET).In-silicoanalysis predicted impaired DNA binding due to W380R mutation. Functional analysis showed that this mutation prevents the ETV6 protein from localizing into the cell nucleus and impairs the transcriptional repression activity of ETV6. Based on the germlineETV6mutation, ET probably started with somaticJAK2V617F mutation, whereas ALL could be caused by diverse mechanisms: high-hyperdiploidity; somatic deletion of exon 1IKZF1gene; or somatic mutations of other genes found by exome sequencing of the ALL sample taken at the diagnosis.
Related projects:	Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VII Searching and functional testing of gene variants predisposing to familial haematopoietic disorders