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. 2025 Jul 23;15:1622820. doi: 10.3389/fonc.2025.1622820

Figure 4.

Diagram illustrating gene mutation pathways leading to anemia and thrombocytosis. It shows SF3B1, ASXL1, JAK2, and CBL mutations affecting splicing, PRC2 disruption, JH2 destabilization, and TKB domain mutation. Pathways illustrate interactions and effects on variables such as mitochondrial iron and STAT5 phosphorylation. Color coding represents distinct pathways and interactions.

SF3B1 clonal dominance modulates ASXL1/JAK2/CBL interplay in MDS/MPN-SF3B1-T. This schematic illustrates the molecular interplay underlying the paradoxical hematologic stability observed in this unique case of SF3B1-mutant MDS/MPN. The dominant SF3B1 p.K700E clone (VAF 40.5%) orchestrates a dual pathogenic cascade: while its spliceosomal dysfunction (via ABCB7/ALAS2 mis-splicing) drives ineffective erythropoiesis, it simultaneously attenuates the leukemogenic potential of the subclonal ASXL1 truncation through erythroid lineage restriction. Concurrently, the JAK2 p.R683G variant exhibits suboptimal kinase activation, which - when coupled with CBL p.R149Q-mediated RAS/MAPK hyperactivation and compensatory JAK2 ubiquitination - generates self-limiting thrombopoiesis. This intricate mutational synergy creates a state of clonal equilibrium, wherein competing oncogenic signals paradoxically maintain disease stability without therapeutic intervention, challenging conventional risk stratification paradigms.