AGK::BRAF fusion activates MAPK signaling, promotes genomic instability, and reduces NIS expression in thyroid cancer cells

Vollständiger Abstract

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Abstract The AGK::BRAF fusion is a recurrent oncogenic alteration in sporadic pediatric papillary thyroid carcinoma (PTC), frequently associated with multifocal disease and pulmonary metastasis. However, the molecular and cellular consequences of AGK::BRAF expression in thyroid follicular cells remain poorly defined. Here, we investigated the biological effects of AGK::BRAF in PCCL3 thyroid cells and compared them with those induced by clinically established pediatric PTC oncogenic drivers, including RET/PTC1, RET/PTC3, ETV6::NTRK3, BRAF V600E, and wild-type BRAF. AGK::BRAF-expressing cells exhibited the most robust MAPK/ERK activation, characterized by markedly enhanced ERK and MEK phosphorylation relative to all other oncogenic drivers analyzed. In contrast, STAT3 and AKT signaling remained comparatively modest and did not show consistent oncogene-specific activation patterns. Functionally, AGK::BRAF expression induced features of thyroid dedifferentiation, including reduced sodium-iodide symporter (NIS) expression and impaired iodide uptake. Concomitantly, AGK::BRAF-expressing cells exhibited increased frequencies of micronuclei and chromatin bridges, together with disruption of three-dimensional telomere architecture, including reduced telomere signal number and intensity, altered spatial organization, and increased nuclear volume. Three-dimensional structured illumination microscopy (3D-SIM) further demonstrated chromatin remodeling, characterized by increased chromatin condensation accompanied by enlarged interchromatin spaces. Collectively, these findings suggest that AGK::BRAF is a dominant oncogenic driver of sustained MAPK/ERK signaling coupled to thyroid dedifferentiation, nuclear architectural remodeling, telomere dysfunction, and genomic instability. These coordinated molecular and structural alterations provide a mechanistic basis for the aggressive clinical course observed in AGK::BRAF-driven pediatric PTC.