ETV6-related thrombocytopenia and platelet dysfunction

Abstract

We and others recently described families with germline heterozygote mutations in ETV6 leading to autosomal dominant highly penetrant thrombocytopenia, red cell macrocytosis and predisposition to leukemia.The bone marrow of affected individuals shows erythroid dysplasia and hyperplasia of small, hypolobulated immature megakaryocytes suggesting a differentiation arrest. This discovery led to subsequent studies that confirmed our findings and to additional larger studies that demonstrated a 1% frequency of germline ETV6 mutations among 4405 individuals with acute lymphoblastic leukemia. Additionally, a 4.5% prevalence of ETV6 germline mutations was reported in families with inherited thrombocytopenia. Preliminary data suggest that decreased ETV6 function leads to MK maturation arrest, impaired platelet production and differentially expressed platelet transcripts among individuals affected with ETV6 mutations when compared to control relatives. Additionally, individuals with some ETV6 mutation exhibit bleeding that appears disproportionate to the mildly reduced platelet count, suggesting a platelet function deficit. Furthermore, recent studies describe decreased ability of platelets from individuals with ETV6 mutations to spread on fibrinogen covered surfaces. Overall, ETV6 germline mutations represent a new cancer predisposition thrombocytopenia with platelet dysfunction.

Keywords: Bleeding; ETV6; thrombocytopenia.

Figure. Transcriptional changes induced by mutant ETV6, overall decreased megakaryocyte and platelet transcripts.

A) RNA clustering among affected individuals with the ETV6 p.P214L mutation compared to unaffected relatives. B) differentially expressed transcripts between affected and unaffected relatives. Gene Set Enrichment Analysis of differentially expressed transcripts in p.P214L platelets compared to control C) erythroid transcripts enriched in patients D) platelet transcripts enriched in controls. E) Genes significantly associated with gene ontology terms. All the genes and pathways in boxes are downregulated in patients with the ETV6 p.P214L mutation when compared to related controls and are overlapped to the megakaryocyte erythroid progenitor to megakaryocyte/platelet pathway as potential sites of action.