To explore the downstream pathways contributing to the tumor-promoting functions of the PIWIL2 fusion product, we focused on two known PIWIL2-binding proteins, NME2 and HDAC3, both of which are implicated in oncogenic signaling—NME2 through its role in metastasis, proliferation, and nucleoside diphosphate kinase activity, and HDAC3 through epigenetic repression of tumor suppressor genes and promotion of cell survival. Here, PIWIL2 is linked to neoplasm.