PHF6, also known as 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 through chromatin state modification, playing a crucial role in neurodevelopment and hematopoiesis [2,5]. In hematopoiesis, it can act as a tumor suppressor protein in some contexts, and its mutations are associated with hematologic malignancies [1].

In mouse models, Phf6 deficiency could delay the progression of RUNX1-ETO9a and MLL-AF9-induced AML, suggesting a pro-oncogenic role in myeloid leukemia as it may maintain AML via regulating the NF-κB signaling pathway [3]. Phf6 knockout also increases the aggressiveness of Hoxa9-driven AML over serial transplantation and expands the leukemia initiating cell-enriched (LIC-e) population, indicating that Phf6 loss increases AML self-renewal [4]. Additionally, Phf6 deficiency promotes JAK3M511I-induced T-ALL progression in mice by inhibiting the Bai1-Mdm2-P53 signaling pathway [6].

In conclusion, PHF6 is a key chromatin-associated factor important for normal development and hematopoiesis. Its role in hematologic malignancies, such as AML and T-ALL, has been illuminated through gene knockout mouse models. These models show that PHF6 can have both tumor-suppressive and pro-oncogenic roles depending on the context, highlighting its complex function in disease development.

References:

1. Kurzer, Jason H, Weinberg, Olga K. 2021. PHF6 Mutations in Hematologic Malignancies. In Frontiers in oncology, 11, 704471. doi:10.3389/fonc.2021.704471. https://pubmed.ncbi.nlm.nih.gov/34381727/

2. Eisa, Yusra A, Guo, Ying, Yang, Feng-Chun. 2022. The Role of PHF6 in Hematopoiesis and Hematologic Malignancies. In Stem cell reviews and reports, 19, 67-75. doi:10.1007/s12015-022-10447-4. https://pubmed.ncbi.nlm.nih.gov/36008597/

3. Hou, Shuaibing, Wang, Xiaomin, Guo, Tengxiao, Sun, Xiaojian, Yuan, Weiping. 2023. PHF6 maintains acute myeloid leukemia via regulating NF-κB signaling pathway. In Leukemia, 37, 1626-1637. doi:10.1038/s41375-023-01953-6. https://pubmed.ncbi.nlm.nih.gov/37393343/

4. Jalnapurkar, Sapana S, Pawar, Aishwarya S, George, Subin S, Gurbuxani, Sandeep, Paralkar, Vikram R. 2024. PHF6 suppresses self-renewal of leukemic stem cells in AML. In Leukemia, 38, 1938-1948. doi:10.1038/s41375-024-02340-5. https://pubmed.ncbi.nlm.nih.gov/39004675/

5. Todd, Matthew A M, Ivanochko, Danton, Picketts, David J. 2015. PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein. In Genes, 6, 325-52. doi:10.3390/genes6020325. https://pubmed.ncbi.nlm.nih.gov/26103525/

6. Yuan, Shengnan, Wang, Xiaomin, Hou, Shuaibing, Cheng, Tao, Yuan, Weiping. 2021. PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression. In Leukemia, 36, 370-382. doi:10.1038/s41375-021-01392-1. https://pubmed.ncbi.nlm.nih.gov/34465864/