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

Abstract

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.

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Fig. 1: Age at diagnosis and anatomic distribution of NTRK3-fused Spitz tumors.
Fig. 2: Spitz melanocytomas (atypical Spitz tumors) with ETV6-NTRK3 fusion.
Fig. 3: Melanocytic tumors with MYO5A-NTRK3 fusion display unique histopathologic features.
Fig. 4: Melanomas with MYO5A-NTRK3 fusion demonstrate nodules of spindled melanocytes with a fascicular growth pattern and areas of marked cytologic atypia.
Fig. 5: Architectural and cytologic features of melanocytic tumors with MYH9-NTRK3 fusion.
Fig. 6: NTRK3 fusions contain different portions of NTRK3 and have distinct subcellular localizations.

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Funding

SP was supported by a grant from the European Academy of Dermatology and Venereology (RF-2017-17). This work was supported by the National Cancer Institute at the National Institutes of Health (Grant Number 1R35CA220481). Immunofluorescence imaging was done at the Nikon Imaging Center, UCSF.

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Correspondence to Iwei Yeh.

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de la Fouchardière, A., Tee, M.K., Peternel, S. et al. Fusion partners of NTRK3 affect subcellular localization of the fusion kinase and cytomorphology of melanocytes. Mod Pathol 34, 735–747 (2021). https://doi.org/10.1038/s41379-020-00678-6

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