Nuclear NPM-ALK Protects Myc from Proteasomal Degradation and Contributes to Its High Expression in Cancer Stem-Like Cells in ALK-Positive Anaplastic Large Cell Lymphoma

• Published in: International journal of molecular sciences Vol. 24; no. 18; p. 14337
• Main Authors: Shang, Chuquan, Lai, Justine, Haque, Moinul, Chen, Will, Wang, Peng, Lai, Raymond
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.09.2023; MDPI
• Subjects: ALK-positive anaplastic lymphoma; Aluminum compounds; Anaplastic Lymphoma Kinase - genetics; Cancer; cancer stemness; Crizotinib; Genotype & phenotype; Half-Life; HEK293 Cells; Humans; Immunoprecipitation; Kinases; Localization; Lymphoma; Lymphoma, Large-Cell, Anaplastic - genetics; Medical research; Myc; Non-Hodgkin's lymphomas; proteasomal degradation; Proteins; Stem cells; proteasomal degradation; Myc; cancer stemness; ALK-positive anaplastic lymphoma
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241814337

In ALK-positive anaplastic large cell lymphoma (ALK+ALCL), a small subset of cancer stem-like (or RR) cells characterized by high Myc expression have been identified. We hypothesize that NPM-ALK contributes to their high Myc expression. While transfection of into HEK293 cells effectively increased Myc by inhibiting its proteosomal degradation (PD-Myc), this effect was dramatically attenuated when the full-length NPM1 (FL-NPM1) was downregulated using shRNA, highlighting the importance of the NPM-ALK:FL-ALK heterodimers in this context. Consistent with this concept, immunoprecipitation experiments showed that the heterodimers are abundant only in RR cells, in which the half-life of Myc is substantially longer than the bulk cells. Fbw7γ, a key player in PD-Myc, is sequestered by the heterodimers in RR cells, and this finding correlates with a Myc phosphorylation pattern indicative of ineffective PD-Myc. Using confocal microscopy and immunofluorescence staining, we found that the fusion signal between ALK and FL-NPM1, characteristic of the heterodimers, correlates with the Myc level in ALK+ALCL cells from cell lines and patient samples. To conclude, our findings have revealed a novel oncogenic function of NPM-ALK in the nucleus. Specifically, the NPM-ALK:FL-NPM1 heterodimers increase cancer stemness by blocking PD-Myc and promoting Myc accumulation in the cancer stem-like cell subset.