Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia

Abstract

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia.1,2 We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B-cell precursor acute lymphoblastic leukemia (ALL). Whole exome sequencing identified a heterozygous single nucleotide change in ETV6 (Ets Variant Gene 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotype found two with ETV6 mutations. One family had the p.Pro214Leu mutation and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA binding domain, with alternative splicing and exon-skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

“…ETV6 mutations are mostly clustered in the DNA-binding and central domains, which abrogates the ETV6 nuclear localization and results in reduced expression of ETV6 and other platelet-associated genes. 44,45 Germline ETV6 mutations have recently been reported as a rare form of inherited thrombocytopenia with predisposition to hematologic malignancy. 44 44 There is no consistent defect in platelet aggregation or activation; platelet spreading appears reduced on fibrinogen but not on collagen and von Willebrand factor.…”

“…44,45 Germline ETV6 mutations have recently been reported as a rare form of inherited thrombocytopenia with predisposition to hematologic malignancy. 44 44 There is no consistent defect in platelet aggregation or activation; platelet spreading appears reduced on fibrinogen but not on collagen and von Willebrand factor. 45 Similar to RUNX1-and AKND26-affected pedigrees, ETV6-related thrombocytopenia is also characterized by normal-sized platelets, 44,45 but electric microscopy shows occasional elongated platelet a granules in affected individuals.…”

Genomics and transcriptomics of megakaryocytes and platelets: Implications for health and disease

“…Mutations in NBEAL2 were determined to be the causative mutation in GPS by next‐generation RNA sequencing of platelets, whole exome sequencing and traditional sequencing strategies, respectively 37, 38, 39. More recently, ETV6 has been implicated in inherited thrombocytopenia using next‐generation sequencing techniques 40, 41…”

Introduction to cancer genetic susceptibility syndromes

“…In several cancer-predisposing conditions, hematopoietic malignancies are included among a spectrum of other neoplasms that can also develop ( Table 2, including ETV6-and PAX5-related familial acute lymphoblastic leukemia (ALL) [8][9][10][11] ; predispositions to acute myeloid leukemia (AML) as a result of germ line mutations in RUNX1, CEBPA, or GATA2 [12][13][14] ; and disorders associated with development of lymphoma, such as X-linked lymphoproliferative disease type 1. Because of space constraints, we direct the reader to several excellent recent reviews for a more comprehensive discussion of the cancer genetic susceptibility syndromes associated with development of these blood cancers.…”