Functional analysis of germline ETV6 W380R mutation causing inherited thrombocytopenia and secondary acute lymphoblastic leukemia or essential thrombocythemia

Abstract

Germline mutations in ETV6 gene cause inherited thrombocytopenia with leukemia predisposition. Here, we report on functional validation of ETV6 W380R mutation segregating with thrombocytopenia in a family where two family members also suffered from acute lymphoblastic leukemia (ALL) or essential thrombocythemia (ET). In-silico analysis 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 germline ETV6 mutation, ET probably started with somatic JAK2 V617F mutation, whereas ALL could be caused by diverse mechanisms: high-hyperdiploidity; somatic deletion of exon 1 IKZF1 gene; or somatic mutations of other genes found by exome sequencing of the ALL sample taken at the diagnosis.

Keywords:

• Acute lymphoblastic leukemia
• ETV6
• myeloproliferative neoplasm
• second hit

Acknowledgements

We thank prof. Zhang (Fred Hutchinson Cancer Research Center, Seattle, Washington, USA) for providing ETV6 variant plasmids.

Authors Contributions

KSK and MD designed and performed experiments, collected, analyzed, interpreted data, wrote and edited the paper; LR, KR, MS, MZK, JB, MP, ZV, FF, SM and SP performed experiments and collected data.

Declaration Of Interest Statement

The authors report no potential conflicts of interest.

Supplemental Material

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Additional information

Funding

This study was supported by Ministry of Health of the Czech Republic, Grant No. [NU20-08-00137], and Masaryk university grant [MUNI/A/1395/2019].