Next generation sequencing has uncovered several genes with associated mutations in hematologic malignancies that can serve as potential biomarkers of disease. Keeping abreast of these genes is therefore of paramount importance in the field of hematology. This review focuses on , a highly conserved epigenetic transcriptional regulator that is important for neurodevelopment and hematopoiesis. 6 serves as a tumor suppressor protein, with mutations and deletions often implicated in the development of T-lymphoblastic leukemia and less frequently in acute myeloid leukemia and other myeloid neoplasms. inactivation appears to be an early event in T-lymphoblastic leukemogenesis, requiring cooperating events, including mutations or overexpression of TLX1 and TLX3 for full disease development. In contrast, mutations tend to occur later in myeloid malignancies, are frequently accompanied by mutations, and are often associated with disease progression. Moreover, 6 appears to play a role in lineage plasticity within hematopoietic malignancies, with mutations commonly present in mixed phenotype acute leukemias with a predilection for T-lineage marker expression. Due to conflicting data, the prognostic significance of mutations remains unclear, with a subset of studies showing no significant difference in outcomes compared to malignancies with wild-type , and other studies showing inferior outcomes in certain patients with mutated Future studies are necessary to elucidate the role plays in development of T-lymphoblastic leukemia, progression of myeloid malignancies, and its overall prognostic significance in hematopoietic neoplasms.