Potent antilymphoma activity of LNS-8801 in ALCL and DLBCL models through a GPER-independent mechanism. (A) Violin plot showing the distribution of IC₅₀ values for LNS-8801 across ALCL, DLBCL, MM, and ALL cell lines. ALCL and DLBCL exhibit significantly lower IC₅₀ values than MM and ALL, indicating higher sensitivity to LNS-8801 (P = .0002). (B) Correlation analysis of GPER mRNA expression and IC₅₀ values of LNS-8801 in ALCL (left panel) and DLBCL (right panel) cell lines. (C) ALCL (Mac-2A and DEL) and DLBCL (OCI-Ly10 and WSU-DLCL2) cell lines were treated with DMSO, LNS-8801 (400 nM), G15 (1 μM), or LNS-8801 in combination with G15 for 72 hours. Cell viability was determined and normalized to the solvent control. (D) GPER KO in Mac-2A using CRISPR/Cas9, the KO efficacy was evaluated by quantitative polymerase chain reaction (left panel), β-actin served as a reference gene. Cytotoxicity of LNS-8801 in GPER KO and WT Mac-2A cells was further assessed after 96 hours of treatment. Data are presented as mean ± standard deviation (A-C,D, left panel) or standard error of the mean (D, right panel) of at least 3 independent experiments. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001, and ∗∗∗∗P < .0001. ALL, acute lymphoblastic leukemia; DMSO, dimethyl sulfoxide; KO, knockout; MM, multiple myeloma; mRNA, messenger RNA; WT, wild-type.