LAUSR

PURPOSE OF REVIEW Even though an increasing amount of sequencing data on the leukemia genome has highlighted a tumor-suppressive function for plant homeodomain finger protein 6 (PHF6), its role in the hematopoietic system remained elusive until recently. The purpose of this review is to describe the role of PHF6 in normal hematopoiesis and leukemogenesis based on recent findings from knockout mouse models. RECENT FINDINGS In a mouse model, the loss of Phf6 enhanced the bone marrow repopulating capacity of hematopoietic stem cells (HSCs) during serial transplantations without transforming hematopoietic cells, whereas donor mice, which lacked Phf6 expression in the hematopoietic system, did not show any apparent phenotypes in the steady-state. Mechanistically, Phf6 activates effectors in the tumor necrosis factor α (Tnfα) pathway. Therefore, a Phf6 deficiency attenuates the expression of the effectors and confers resistance against Tnfα-mediated growth inhibition to HSCs. Moreover, the loss of Phf6 promoted the development of leukemia induced by aberrant TLX3 expression or an active NOTCH mutation. SUMMARY Phf6 restricts the self-renewal of HSCs by governing the Tnfα pathway. Phf6 fulfills a tumor-suppressive function, and its loss synergizes with leukemic lesions to promote the onset of hematological malignancies.