{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSETBP1 acts as a potent oncogenic driver in hematopoietic malignancies. In several studies involving patients with atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and even secondary acute myeloid leukemia, recurrent somatic gain‐of‐function mutations in SETBP1 were shown to promote clonal expansion through several mechanisms. These include enhanced self‐renewal, inhibition of the tumor suppressor PP2A, and deregulation of key transcription factors (such as HOXA genes, RUNX1, and MYB) that control proliferation and differentiation. Moreover, SETBP1 mutations may be acquired as secondary events during leukemic evolution and can even occur as part of fusion transcripts (e.g., HMGA2–SETBP1 in lipomas), further underscoring its role in driving oncogenic transformation and serving as an important diagnostic and prognostic biomarker in myeloid diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the developmental context, germline de novo and haploinsufficient alterations in SETBP1 underlie distinct neurodevelopmental syndromes. Deleterious SETBP1 variants are responsible for Schinzel–Giedion syndrome—a severe multisystem disorder characterized by profound intellectual disability and congenital malformations—where the mutations predominantly act via a gain‐of‐function mechanism. Conversely, deletion or loss‐of‐function mutations affecting SETBP1 lead to a milder phenotype with expressive speech impairment, motor delays, and subtle dysmorphic features. Additional studies have also linked common SETBP1 polymorphisms to variations in phonological working memory and reading-related brain activation, highlighting a broader role in neurodevelopment and tissue-specific transcriptional regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThus, SETBP1 emerges as a context‐dependent regulator whose dosage and mutational status determine diverging biological outcomes. In hematologic tissues, somatic gain‐of‐function mutations lead to the activation of proliferative and anti‐differentiation pathways—often in synergy with other oncogenic lesions—while in the developing brain, both hyperstabilization and haploinsufficiency of SETBP1 disrupt normal transcriptional programs and epigenetic remodeling, thereby impairing neural progenitor function and culminating in neurodevelopmental disorders. This dual role as an epigenetic and transcriptional regulator highlights SETBP1’s importance as a diagnostic marker and potential therapeutic target across a spectrum of diseases.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marion G Ott, Manfred Schmidt, Kerstin Schwarzwaelder, et al. 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