PHF6, short for Plant homeodomain finger protein 6, is a member of the plant homeodomain (PHD)-like zinc finger family of proteins. It is involved in transcriptional regulation by modifying the chromatin state. PHF6 is crucial for neurodevelopment and hematopoiesis, acting as an epigenetic transcriptional regulator [2,5].

In hematological malignancies, PHF6 mutations have been identified in various types of leukemia. In T-lymphoblastic leukemia, PHF6 inactivation seems to be an early event, often requiring additional events like NOTCH1 mutations for full disease development [1]. In myeloid malignancies, PHF6 mutations occur later, frequently accompany RUNX1 mutations, and are associated with disease progression [1]. In acute myeloid leukemia (AML) mouse models, Phf6 deficiency could delay the progression of RUNX1-ETO9a and MLL-AF9-induced AML. PHF6 depletion inhibited the NF-κB signaling pathways, suggesting a pro-oncogenic role in myeloid leukemia [3]. Also, Phf6 knockout in Hoxa9-driven AML mouse models increased the aggressiveness of the disease over serial transplantation and the frequency of leukemia initiating cells [4].

In conclusion, PHF6 is a key chromatin-associated factor important for normal neurodevelopment and hematopoiesis. Its role in hematological malignancies, especially in T-lymphoblastic leukemia and AML, has been revealed through gene knockout mouse models. These models help us understand how PHF6 mutations contribute to disease development and progression, providing potential targets for treating these malignancies [1,3,4].