CAPN1 promotes the progression of MLL-rearranged acute myeloid leukemia by suppressing SHP-1 and activating MAPK/ERK signaling pathway.

BACKGROUND: The MLL-rearranged (MLL-r) acute myeloid leukemia (AML) represents a hematological malignancy with a dismal prognosis and a pressing demand for innovative therapeutic targets. CAPN1 is overexpressed in MLL-r AML and predicts poor prognosis, however, its roles in MLL-r AML remains unclear. METHODS: Prognostic value of CAPN-1 was evaluated using logistic regression and receiver operating characteristic (ROC) analyses. Roles of CAPN-1 were assessed in MOLM13, MV4-11 and NOMO-1 cells with CAPN-1 knockdown or overexpressed using CCK-8, colony formation, flow cytometry, and CDX mouse models. Mechanistic studies were conducted via RNA sequencing, co-IP, IF and molecular docking, focusing on the CAPN1-SHP-1-MAPK/ERK signaling axis. RESULTS: The expression of CAPN1 was the highest in the MLL-r subtype among different AML subtypes, correlating with adverse clinical outcomes. CAPN1 knockdown markedly suppressed proliferation and clonogenic capacity, induced apoptosis, and caused G2/M arrest, whereas CAPN1 overexpression displayed opposite results, and this pro-leukemic functions were dependent on its proteolytic activity. In vivo, CAPN1 knockdown prolonged survival and reduced leukemic infiltration of mouse in xenograft models, while its overexpression accelerated disease progression. Mechanistically, CAPN1 directly interacted with SHP-1 and reduced its stability via protease function, thereby enhancing MAPK/ERK phosphorylation. Pharmacological reactivation of ERK signaling by ceramide C6 treatment rescued the apoptosis and G2/M arrest induced by CAPN1 knockdown. CONCLUSION: CAPN1 acts as a novel prognostic biomarker and oncogenic driver in MLL-r AML by interacting with and suppressing SHP-1 to activate the MAPK/ERK pathway, highlighting the CAPN1-SHP-1-MAPK/ERK axis as a promising therapeutic target in the MLL-r AML subtype.