Fusion partners of NTRK3 affect subcellular localization of the fusion kinase and cytomorphology of melanocytes

Mod Pathol. 2021 Apr;34(4):735-747. doi: 10.1038/s41379-020-00678-6. Epub 2020 Sep 23.


A subset of Spitz tumors harbor fusions of NTRK3 with ETV6, MYO5A, and MYH9. We evaluated a series of 22 melanocytic tumors in which an NTRK3 fusion was identified as part of the diagnostic workup. Tumors in which NTRK3 was fused to ETV6 occurred in younger patients were predominantly composed of epithelioid melanocytes and were classified by their histopathologic features as Spitz tumors. In contrast, those in which NTRK3 was fused to MYO5A were predominantly composed of spindled melanocytes arrayed in fascicles with neuroid features such as pseudo-Verocay bodies. To further investigate the effects of the fusion kinases ETV6-NTRK3 and MYO5A-NTRK3 in melanocytes, we expressed them in immortalized melanocytes and determined their subcellular localization by immunofluorescence. ETV6-NTRK3 was localized to the nucleus and diffusely within the cytoplasm and caused melanocytes to adopt an epithelioid cytomorphology. In contrast, MYO5A-NTRK3, appeared excluded from the nucleus of melanocytes, was localized to dendrites, and resulted in a highly dendritic cytomorphology. Our findings indicate that ETV6-NTRK3 and MYO5A-NTRK3 have distinct subcellular localizations and effects on cellular morphology.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • Cell Line
  • Cell Shape
  • Child
  • Child, Preschool
  • Female
  • Gene Fusion*
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Melanocytes / pathology*
  • Middle Aged
  • Myosin Heavy Chains / genetics*
  • Myosin Type V / genetics*
  • Nevus, Epithelioid and Spindle Cell / enzymology
  • Nevus, Epithelioid and Spindle Cell / genetics*
  • Nevus, Epithelioid and Spindle Cell / pathology
  • Oncogene Proteins, Fusion / genetics*
  • Phenotype
  • Receptor, trkC / genetics*
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Young Adult


  • Biomarkers, Tumor
  • ETV6-NTRK3 fusion protein, human
  • NTRK3 protein, human
  • Oncogene Proteins, Fusion
  • MYO5A protein, human
  • Receptor, trkC
  • Myosin Type V
  • Myosin Heavy Chains