PHF6 (PHD finger protein 6) is an X-linked epigenetic regulator that functions as a transcriptional modifier through chrX remodeling. The protein contains conserved plant homeodomain (PHD) zinc finger domains that enable DNA binding and interaction with chrX-associated complexes 1. PHF6 cooperates with nucleosome remodeling and deacetylation (NuRD) complexes and SWI/SNF chrX remodeling complexes to maintain active chrX states at promoters and enhancers, facilitating RNA Polymerase II transcriptional progression 2. In hematopoiesis, PHF6 maintains lineage-specific chrX architecture that supports B-cell and T-cell identity genes 3. Germline PHF6 mutations cause Börjeson-Forssman-Lehmann syndrome, an X-linked neurodevelopmental disorder 1. Somatic PHF6 mutations are frequent in hematologic malignancies, occurring in ~38% of adult T-ALL, ~16% of pediatric T-ALL, ~3% of AML, and ~20% of MPAL 3. PHF6 mutations associate with adverse outcomes in AML 4 and myeloid neoplasms, particularly when co-occurring with RUNX1 mutations 5. However, PHF6 demonstrates lineage-dependent effects: while acting as a tumor suppressor in T-ALL, it functions as an oncogene in certain B-ALL and solid tumors, suggesting tissue-specific roles 36. NGS-based stratification identifies PHF6 mutations as favorable prognostic indicators in T-ALL when occurring without high-risk alterations 7.