ASXL2 is an epigenetic regulator and component of the PR-DUB (Polycomb repressive deubiquitinase) complex that functions as a transcriptional coactivator 12. As a putative Polycomb group protein, ASXL2 maintains transcriptionally repressive chr2 states through histone modification, particularly via deubiquitination of histone H2A at lysine 119 (H2AK119ub1) 12. ASXL2 enhances adipocyte differentiation by acting as a coactivator for peroxisome proliferator-activated receptor gamma (PPARG) through differential recruitment of acetylated and methylated histone H3 [UniProt]. Additionally, ASXL2 recruits the deubiquitinase BAP1 to active enhancers through interaction with MLL3/4 complexes 3. The protein also regulates retinoic acid signaling during cardiac development 4. Recurrent ASXL2 mutations occur in core-binding factor acute myeloid leukemia (CBF-AML), particularly in RUNX1-RUNX1T1 cases, suggesting a cooperating role in leukemogenesis 56. ASXL2 is located on chromosome 2.3, a recombination hotspot associated with carcinogenesis 7. Loss-of-function ASXL2 variants cause Shashi-Pena syndrome, characterized by developmental delay, cardiac dysfunction, and feeding difficulties 8.