CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma
Abstract Background Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. Methods Cell proliferation, drug resistance, and chromosomal ins...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-06-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-021-01380-0 |
| _version_ | 1818597215055118336 |
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| author | Chunyan Gu Wang Wang Xiaozhu Tang Tingting Xu Yanxin Zhang Mengjie Guo Rongfang Wei Yajun Wang Artur Jurczyszyn Siegfried Janz Meral Beksac Fenghuang Zhan Anja Seckinger Dirk Hose Jingxuan Pan Ye Yang |
| author_facet | Chunyan Gu Wang Wang Xiaozhu Tang Tingting Xu Yanxin Zhang Mengjie Guo Rongfang Wei Yajun Wang Artur Jurczyszyn Siegfried Janz Meral Beksac Fenghuang Zhan Anja Seckinger Dirk Hose Jingxuan Pan Ye Yang |
| author_sort | Chunyan Gu |
| collection | DOAJ |
| description | Abstract Background Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. Methods Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. Results We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. Conclusions Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche. |
| first_indexed | 2024-12-16T11:44:15Z |
| format | Article |
| id | doaj.art-3d70242196df4660b1542e1e21333f89 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-16T11:44:15Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-3d70242196df4660b1542e1e21333f892022-12-21T22:32:51ZengBMCMolecular Cancer1476-45982021-06-0120111410.1186/s12943-021-01380-0CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myelomaChunyan Gu0Wang Wang1Xiaozhu Tang2Tingting Xu3Yanxin Zhang4Mengjie Guo5Rongfang Wei6Yajun Wang7Artur Jurczyszyn8Siegfried Janz9Meral Beksac10Fenghuang Zhan11Anja Seckinger12Dirk Hose13Jingxuan Pan14Ye Yang15Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineNanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineDepartment of Hematology, Jagiellonian University Medical CollegeDivision of Hematology and Oncology, Medical College of WisconsinDepartment of Hematology, School of Medicine, Ankara UniversityMyeloma Center, University of Arkansas for Medical SciencesLaboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB)Laboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB)Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese MedicineNanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese MedicineAbstract Background Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. Methods Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. Results We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. Conclusions Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.https://doi.org/10.1186/s12943-021-01380-0Multiple myelomaCHEK1circCHEK1_246aaProliferationDrug resistanceChromosomal instability |
| spellingShingle | Chunyan Gu Wang Wang Xiaozhu Tang Tingting Xu Yanxin Zhang Mengjie Guo Rongfang Wei Yajun Wang Artur Jurczyszyn Siegfried Janz Meral Beksac Fenghuang Zhan Anja Seckinger Dirk Hose Jingxuan Pan Ye Yang CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma Molecular Cancer Multiple myeloma CHEK1 circCHEK1_246aa Proliferation Drug resistance Chromosomal instability |
| title | CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma |
| title_full | CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma |
| title_fullStr | CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma |
| title_full_unstemmed | CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma |
| title_short | CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma |
| title_sort | chek1 and circchek1 246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma |
| topic | Multiple myeloma CHEK1 circCHEK1_246aa Proliferation Drug resistance Chromosomal instability |
| url | https://doi.org/10.1186/s12943-021-01380-0 |
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