Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction
Abstract 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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-05-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02247-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849733812095811584 |
|---|---|
| author | Boxuan Wei Qingxiong Yu Jiamin Jin Danli Zhu Bohan Lai Jieyu Gu Ran Yang Huailiang Huang Hongzhan Lin Liang Zhang Tao Zan Feng Xie Kang Zhang Qingfeng Li |
| author_facet | Boxuan Wei Qingxiong Yu Jiamin Jin Danli Zhu Bohan Lai Jieyu Gu Ran Yang Huailiang Huang Hongzhan Lin Liang Zhang Tao Zan Feng Xie Kang Zhang Qingfeng Li |
| author_sort | Boxuan Wei |
| collection | DOAJ |
| description | Abstract 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 anti-apoptotic 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 V600E-mutated transgenic models following BCL2i treatment. Histology of regressed GCMN indicated extensive immune cell infiltration, 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. Long-term 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. |
| format | Article |
| id | doaj-art-28769c736fed424cb2ff3285cae2bb81 |
| institution | DOAJ |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-28769c736fed424cb2ff3285cae2bb812025-08-20T03:07:57ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-05-0110111510.1038/s41392-025-02247-2Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune inductionBoxuan Wei0Qingxiong Yu1Jiamin Jin2Danli Zhu3Bohan Lai4Jieyu Gu5Ran Yang6Huailiang Huang7Hongzhan Lin8Liang Zhang9Tao Zan10Feng Xie11Kang Zhang12Qingfeng Li13Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineCAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of SciencesDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineCenter for Biomedicine and Innovations, Faculty of Medicine, Macau University of Science and TechnologyDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineAbstract 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 anti-apoptotic 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 V600E-mutated transgenic models following BCL2i treatment. Histology of regressed GCMN indicated extensive immune cell infiltration, 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. Long-term 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.https://doi.org/10.1038/s41392-025-02247-2 |
| spellingShingle | Boxuan Wei Qingxiong Yu Jiamin Jin Danli Zhu Bohan Lai Jieyu Gu Ran Yang Huailiang Huang Hongzhan Lin Liang Zhang Tao Zan Feng Xie Kang Zhang Qingfeng Li Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction Signal Transduction and Targeted Therapy |
| title | Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction |
| title_full | Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction |
| title_fullStr | Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction |
| title_full_unstemmed | Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction |
| title_short | Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction |
| title_sort | anti bcl2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction |
| url | https://doi.org/10.1038/s41392-025-02247-2 |
| work_keys_str_mv | AT boxuanwei antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT qingxiongyu antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT jiaminjin antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT danlizhu antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT bohanlai antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT jieyugu antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT ranyang antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT huailianghuang antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT hongzhanlin antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT liangzhang antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT taozan antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT fengxie antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT kangzhang antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction AT qingfengli antibcl2therapyeliminatesgiantcongenitalmelanocyticnevusbysenolyticandimmuneinduction |