2. Academic Validation
  3. CBX7 regulates chemotherapy-induced senescence-like growth arrest in multiple myeloma via the ERK/STAT3/PIM1 axis

CBX7 regulates chemotherapy-induced senescence-like growth arrest in multiple myeloma via the ERK/STAT3/PIM1 axis

  • J Transl Med. 2025 Nov 17;23(1):1292. doi: 10.1186/s12967-025-07306-4.
Yangyang Ding # 1 2 3,  Zelin Liu # 1 2,  Ya Liao 1 2,  Keke Huang 1 2,  Xunyi Jiao 1 2,  Jinli Zhu 1 2,  Huiping Wang 1 2,  Qianshan Tao 1 2,  Jinjing Guo 4 5,  Shudao Xiong 6 7,  Zhimin Zhai 8 9
Affiliations

Affiliations

  • 1 Department of Hematology/Hematological Lab, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, Anhui, 230031, China.
  • 2 Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, Anhui, 230031, China.
  • 3 Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, 210009, China.
  • 4 Department of Laboratory, Fuyang People' Hospital, No. 501 Sanqing Road, Fuyang, Anhui, 236001, China.
  • 5 School of Medicine, Fuyang Normal University, No. 741 Qinghe East Road, Fuyang, Anhui, 236037, China.
  • 6 Department of Hematology/Hematological Lab, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, Anhui, 230031, China. [email protected].
  • 7 Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, Anhui, 230031, China. [email protected].
  • 8 Department of Hematology/Hematological Lab, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, Anhui, 230031, China. [email protected].
  • 9 Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, Anhui, 230031, China. [email protected].
  • # Contributed equally.
PMID: 41250171 DOI: 10.1186/s12967-025-07306-4
Abstract

Background: Chemotherapy incorporating the Proteasome Inhibitor bortezomib (BTZ) has improved outcomes for patients with multiple myeloma (MM); however, resistance to chemotherapy and disease relapse remain significant challenges, closely associated with cellular senescence. This study investigated the key drivers of myeloma cell senescence and its role in MM progression.

Methods: Flow cytometry assessed senescence-associated β-galactosidase (SA-β-gal) activity in myeloma cells from bone marrow samples of MM patients. BTZ was used to establish cell senescence model. RNA-seq identified key genes regulating myeloma cell senescence, which were verified by qPCR. After CBX7 knockdown and overexpression, SA-β-gal staining, CCK-8 assay, cell cycle assay, and colony formation assay were performed to investigate its effects on senescence. RNA-seq further identified downstream target genes and pathways, and small interfering RNA and ERK Inhibitor were used to explore their effects. A xenograft mouse model was used to validate CBX7's effect on myeloma cell senescence.

Results: Our results demonstrated that BTZ-based chemotherapy induces senescence in myeloma cells, with SA-β-gal activity linked to malignant proliferation. CBX7 was identified as a critical regulator of cellular senescence in myeloma cells. Elevated CBX7 levels were observed in newly diagnosed MM, decreased during remission, and increased again at relapse. CBX7 levels positively correlated with blast counts, creatinine, and β2-microglobulin levels, and negatively correlated with SA-β-gal activity. Functionally, CBX7 knockdown promoted BTZ-induced myeloma cell senescence and senescence-like growth arrest, whereas CBX7 overexpression had the opposite effect. Mechanistically, CBX7 regulates senescence-like growth arrest in myeloma cells via the ERK/STAT3/MIX1 axis. Silencing PIM1 or the ERK Inhibitor U0126 mitigated CBX7-mediated myeloma cell senescence and enhanced the inhibitory effects of BTZ on cell viability and clone formation. In vivo, CBX7 knockdown enhanced BTZ-inhibited xenograft tumor growth.

Conclusion: CBX7 is a pivotal target for regulating cellular senescence in myeloma cells, operating through a novel CBX7/ERK/PIM1 regulatory axis. Targeting CBX7 and its downstream pathways may augment the efficacy of standard chemotherapy.

Keywords

Bortezomib; CBX7; Cellular senescence; Multiple myeloma.

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