LCP2 mediates SUV39H1-driven cellular senescence-related chemoresistance in natural killer/T-cell lymphoma.

Preclinical study involving in vitro cell line experiments and in vivo mouse models to investigate mechanisms of chemoresistance in NKTCL.

“Here, we demonstrate that chemoresistant NKTCL cells acquire phenotypic senescence features.”

NKTCL cell lines (NKYS, KHYG-1, SNK-6, SNT16, RMA), human plasma and tissue samples from NKTCL patients, and C57BL/6J-Lcp2em1 mice.

“NKYS and KHYG-1 cell lines were kindly provided by Dr. Wing C. Chan (City of Hope Medical Centre).”

48 plasma samples per group (CR and R/R) for proteomic and ELISA validation; 5 mice per group for in vivo tumour models.

“WB and ELISA analyses were performed to detect LCP2 protein expression in plasma samples from additional patients.”

In vivo tumour growth monitored over approximately 20-30 days, with ADM treatment administered from day 5 to day 9.

“However, after ADM treatment (administered from day 5 to day 9) in the shCtrl+ADM and shLcp2+ADM groups, the shLcp2+ADM group exhibited significantly greater chemoresistance compared with the shCtrl+ADM group”

LCP2 expression is significantly reduced in the plasma of relapsed/refractory NKTCL patients and in chemoresistant cells, correlating inversely with the senescence marker SA-β-gal.

“Of these, LCP2 expression was significantly reduced in the plasma of R/R NKTCL patients and in chemoresistant cells, correlating inversely with senescence marker SA-β-gal.”

LCP2 deficiency activates the IQGAP2/LaminA/C/SUV39H1 axis, driving DNA damage, telomere stress-induced senescence, and the formation of an immunosuppressive microenvironment.

“Mechanistically, LCP2 deficiency activated the IQGAP2/LaminA/C/SUV39H1 axis, thus driving DNA damage, telomere stress-induced senescence, and facilitating the formation of an immunosuppressive microenvironment.”

Targeting the LCP2-mediated axis with Epitalon and Chaetocin partially eliminates therapy-induced senescent cells and enhances response to chemotherapeutics in vivo.

“Importantly, targeting this axis with Epitalon and Chaetocin can partially eliminate therapy-induced senescent cells, enhance response to chemotherapeutics, and alleviate the immunosuppressive microenvironment to a certain extent in vivo.”

SASP factor expression shows heterogeneity among cell lines, the mechanism of LCP2 downregulation in plasma is unclear, and precise phosphorylation regulatory mechanisms require further investigation.

“First, SASP factor expression has heterogeneity [41], which varies among different NKTCL cell lines and T cells (Fig. 1D).”