The ETV6 gene (previously known as TEL) belongs to the ETS (E26 transformation specific) family of transcription factors characterized by 2 important domains: the C-terminal Ets domain responsible for specific DNA-binding activities and the N-terminal helix–loop–helix (HLH) oligomerization domain, also known as pointed (PNT) or sterile alpha motif (SAM), that mediates protein–protein interaction with Ets factors. 1-3 The ETV6 protein plays a crucial role in the embryonic development and hematopoietic regulation. 4 ETV6 is also a versatile element at the center of a network of genes involved in hematologic malignancies through diverse molecular mechanisms, such as fused with other genes and deletions. 3, 5-8 ETV6 was originally identified as a fusion partner of the gene that is fused to PDGFRB (platelet derived growth factor receptor beta) gene in chronic myelomonocytic leukemia (CMML) patients with t (5; 12)(q33; p13). 8 Subsequently, a growing number of genes have been identified as fusion partners of ETV6. At present, 30 partner genes of the ETV6 gene have been described in a broad spectrum of hematopoietic malignancies. 9 Deregulation of the ETV6 gene through deletion is also recurrent in leukemia, especially in acute lymphoblastic leukemia patients with t (12; 21)(p13; q22). 10 Recently, point mutations in the ETV6 gene have been reported in 2.7% cases of myelodysplastic syndromes (MDS), 11 24-33% of early T-cell precursor ALL (ETPALL), 12, 13 and a few cases of acute myelogenous leukemia (AML). 14 However, only few data are available on other entities of hematologic malignancies. In order to analyze the frequency of ETV6 mutations and their clinical impact, we investigated a total of 970 cases. In detail, we analyzed 296 de novo AML, 139 B-cell acute lymphoblastic leukemia (B-ALL), 53 T-cell acute lymphoblastic leukemia (T-ALL), 37 mixed-phenotype acute leukemia (MPAL), 169 chronic myeloid leukemia (CML), 101 MDS, 49 chronic lymphocytic leukemia (CLL), 62 myeloproliferative neoplasms (MPN), 28 multiple myeloma (MM), and 36 non-Hodgkin lymphoma (NHL) cases. There were 462 male and 501 female patients in this series; median age was 44 years (range 5-88 years). Main patients’ characteristics are summarized in Table 1.