Abstract
Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germline ETV6 p. L349P mutation in a kindred affected by thrombocytopenia and ALL. A second ETV6 p. N385fs mutation was identified in an unrelated kindred characterized by thrombocytopenia, ALL and secondary myelodysplasia/acute myeloid leukemia. Leukemic cells from the proband in the second kindred showed deletion of wild type ETV6 with retention of the ETV6 p. N385fs. Enforced expression of the ETV6 mutants revealed normal transcript and protein levels, but impaired nuclear localization. Accordingly, these mutants exhibited significantly reduced ability to regulate the transcription of ETV6 target genes. Our findings highlight a novel role for ETV6 in leukemia predisposition.
Highlights
Acute leukemias comprise the most common form of pediatric cancer, among which acute lymphoblastic leukemia (ALL) makes up 80–85% of the cases[1,2]
Inherited mutations of transcription factors have recently been associated with susceptibility to acute leukemia
The mutant proteins showed decreased ability to regulate the expression of other genes typically suppressed by ETV6. These findings suggest that germline ETV6 mutations cause a new type of heritable leukemia
Summary
Acute leukemias comprise the most common form of pediatric cancer, among which acute lymphoblastic leukemia (ALL) makes up 80–85% of the cases[1,2]. Acute leukemia presents in the context of thrombocytopenia Consistent with this feature, several heritable thrombocytopenia syndromes are known to exist, some of which are associated with an increased incidence of leukemia. Genes associated with these syndromes include RUNX1, ANKRD26, GATA1, MPL, HOXA11 and RMB8A[9,10,11,12,13,14,15,16]. Functional studies support a pathogenic role for the observed mutations, both of which affect the DNA binding domain These findings are consistent with independent observations describing additional kindreds characterized by thrombocytopenia and predisposition to hematopoietic malignancy[17,18] and provide insights into the mechanisms of leukemia susceptibility and clinical phenotypes associated with germline ETV6 mutations[19]
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