Giant congenital melanocytic nevus(GCMN)is a RAS/RAF mutation-driven syndrome characterized by extensive melanocytic lesions,posing psychological challenges and a lifelong risk of malignancy.Existing treatments like s...Giant congenital melanocytic nevus(GCMN)is a RAS/RAF mutation-driven syndrome characterized by extensive melanocytic lesions,posing psychological challenges and a lifelong risk of malignancy.Existing treatments like surgical resection and laser therapy fail to fully remove lesions,and MAPK inhibitors show limited efficacy.This study identified a predominant population of senescent cells and a minority of proliferative cells in GCMN,necessitating dual-targeted strategies.We found that the antiapoptotic protein BCL2 is expressed in both senescent and proliferative cells from GCMN patients with various gene mutations.Coexpression of P16 and BCL2 indicated a phenotype of growth arrest and cell survival.BCL2 inhibitors(BCL2i)showed significant cytotoxicity to GCMN cells in vitro.Hypopigmentation and GCMN cell clearance were observed in patient-derived xenograft models and in Nras^(Q61K)-mutated and Braf^(V600)E-mutated transgenic models following BCL2i treatment.Histology of regressed GCMN indicated extensive immune cell infltration,suggesting immune involvement.Single-cell sequencing and immunostaining revealed that activated neutrophils formed extracellular traps,synergizing with BCL2i to treat GCMN.Neutrophil depletion and immunosuppression reduce treatment efficacy,highlighting the crucial role of the immune response post-BCL2i treatment.Longterm follow-up showed no recurrence,with neutrophils and T cells residing in the dermis,indicating memory immune reactions.These findings present a promising therapeutic strategy and underscore the translational potential of BCL2i in treating GCMN.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.81871595,82372533)the Shanghai Clinical Research Center of Plastic and Reconstructive Surgery affliated to Science and Technology Commission of Shanghai Municipality(GrantNo.22MC1940300).
文摘Giant congenital melanocytic nevus(GCMN)is a RAS/RAF mutation-driven syndrome characterized by extensive melanocytic lesions,posing psychological challenges and a lifelong risk of malignancy.Existing treatments like surgical resection and laser therapy fail to fully remove lesions,and MAPK inhibitors show limited efficacy.This study identified a predominant population of senescent cells and a minority of proliferative cells in GCMN,necessitating dual-targeted strategies.We found that the antiapoptotic protein BCL2 is expressed in both senescent and proliferative cells from GCMN patients with various gene mutations.Coexpression of P16 and BCL2 indicated a phenotype of growth arrest and cell survival.BCL2 inhibitors(BCL2i)showed significant cytotoxicity to GCMN cells in vitro.Hypopigmentation and GCMN cell clearance were observed in patient-derived xenograft models and in Nras^(Q61K)-mutated and Braf^(V600)E-mutated transgenic models following BCL2i treatment.Histology of regressed GCMN indicated extensive immune cell infltration,suggesting immune involvement.Single-cell sequencing and immunostaining revealed that activated neutrophils formed extracellular traps,synergizing with BCL2i to treat GCMN.Neutrophil depletion and immunosuppression reduce treatment efficacy,highlighting the crucial role of the immune response post-BCL2i treatment.Longterm follow-up showed no recurrence,with neutrophils and T cells residing in the dermis,indicating memory immune reactions.These findings present a promising therapeutic strategy and underscore the translational potential of BCL2i in treating GCMN.
