Introduction: PTPN2 was identified as the essential gene for the growth and survival of ALK+ALCL based on the results of the whole genome loss of function screens in ALK+ALCL cells (SUDHL1, Karpas299, KIJK, SUPM2 and DEL). The first in class potent PTPN2/1 active site inhibitor ABBV CLS 484 (AC484) has also shown promising prospects for cancer treatments in tumors (NCT04777994). Methods: Gene knockout was achieved by CRISPR/Cas9 system. RNA sequencing was performed following PTPN2 knockout. Wild type and PTPN2 knockout cells were injected subcutaneously into NOD/SCID male mice. scRNA-seq was performed on Karpas299 treated with AC484. Objectives: The study aims to explore the role and underlying mechanism of PTPN2 and the efficacy of AC484 in ALK+ALCL. Results: High PTPN2 expression was observed in ALK+ALCL cell lines and patients. Functional assays demonstrated that PTPN2 depletion or AC484 treatment inhibited tumor cell proliferation, promoted apoptosis, and induced cell cycle arrest. The mice in the AC484 treated group showed significant tumor growth rate and tumor regression. KEGG analysis showed significant enrichment in the Mitophagy pathway following PTPN2 knockout or treated with AC484. LC3 II expression was significantly downregulated in mitochondria by PTPN2 knockout in the presence of Bafilomycin A1 (BafA1). Since TFRC was reported as a mitochondrial regulator (Senyilmaz D, Nature), we identified that PTPN2 negatively regulated TFRC expression by transcription factor HIF1A and PTPN2 deficiency resulted in PINK1 PRKN mediated mitophagy inhibition and damaged mitochondria clearance through disinhibiting TFRC expression. Conclusion: AC484 showed a great anti tumor effect against ALK+ALCL by disrupting mitochondrial function and mitophagy.
