{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ASXL2 is a member of the Additional Sex Combs‐Like family that functions as an essential epigenetic scaffold integrating multiple signals to regulate chromatin and gene expression. In several studies, ASXL2 was shown to interact with the deubiquitinase BAP1 and other epigenetic regulators to promote the removal of repressive histone marks such as monoubiquitinated H2A and to facilitate proper deposition of trimethylated histone H3 lysine 27."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the hematopoietic system, recurrent somatic mutations in ASXL2 have been identified predominantly in core‐binding factor acute myeloid leukemia—especially in t(8;21) cases—where loss or alteration of ASXL2 function disrupts normal gene regulation and contributes to leukemogenesis and myelodysplastic syndrome–like phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in leukemogenesis, ASXL2 also contributes critically to metabolic and skeletal homeostasis. In bone, genetic association studies and experimental loss‐of‐function analyses in mouse models have implicated ASXL2 as a positive regulator of osteoclast differentiation and mitochondrial biogenesis, thereby affecting bone remodeling and mineral density."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": " In adipose tissue, ASXL2 enhances peroxisome proliferator–activated receptor γ (PPARγ) activity to promote adipogenesis, and genetic variants at the ASXL2 locus have been associated with altered circulating IGF-I levels, reduced adiposity, and increased longevity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the heart, ASXL2 is highly expressed and participates in the recruitment of Polycomb repressive complexes to target gene promoters. Loss of ASXL2 disrupts the conversion of histone H3 lysine 27 di- to trimethylation and impairs deubiquitination of histone H2A, leading to de-repression of key cardiac genes and contributing to cardiac dysfunction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Germline de novo truncating variants in ASXL2 have recently been linked to a clinically recognizable neurodevelopmental syndrome characterized by macrocephaly, dysmorphic facial features, feeding difficulties, hypotonia, and developmental delays, underscoring its critical function during development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings support a multifaceted role for ASXL2 as a master regulator that integrates epigenetic control with metabolic, skeletal, hematopoietic, and cardiac gene programs. Its dysregulation—whether through somatic mutations or germline variants—can therefore contribute to diverse pathologies including leukemia, metabolic disorders, cardiac dysfunction, and developmental syndromes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}, {"type": "fg_f", "ref": "15"}, {"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anwesha Dey, Dhaya Seshasayee, Rajkumar Noubade, et al. 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