Establishment of a Bortezomib-Resistant Multiple Myeloma Xenotransplantation Mouse Model by Transplanting Primary Cells from Patients.
10.19746/j.cnki.issn.1009-2137.2025.01.019
- Author:
Yan-Hua YUE
1
;
Yi-Fang ZHOU
1
;
Ying-Jie MIAO
1
;
Yang CAO
1
;
Fei WANG
1
;
Yue LIU
1
;
Feng LI
1
;
Yang-Ling SHEN
1
;
Yan-Ting GUO
1
;
Yu-Hui HUANG
2
;
Wei-Ying GU
1
Author Information
1. Department of Hematology, The Third Affiliated Hospital of Soochow University/The First People's Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China.
2. Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
- Publication Type:Journal Article
- Keywords:
multiple myeloma;
bortezomib resistance;
patient-derived xenotransplantation model;
anlotinib
- MeSH:
Animals;
Bortezomib;
Humans;
Multiple Myeloma/pathology*;
Mice;
Apoptosis;
Drug Resistance, Neoplasm;
Cell Line, Tumor;
Xenograft Model Antitumor Assays;
Mice, Inbred NOD;
Disease Models, Animal;
Cell Proliferation;
Transplantation, Heterologous
- From:
Journal of Experimental Hematology
2025;33(1):133-141
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To explore the construction method of a resistant multiple myeloma (MM) patient-derived xenotransplantation (PDX) model.
METHODS:1.0×107 MM patient-derived mononuclear cells (MNCs), 2.0×106 MM.1S cells and 2.0×106 NCI-H929 cells were respectively subcutaneously inoculated into NOD.CB17-Prkdcscid Il2rgtm1/Bcgen (B-NDG) mice with a volume of 100 μl per mouse to establish mouse model. The morphologic, phenotypic, proliferative and genetic characteristics of PDX tumor were studied by hematoxylin-eosin staining, immunohistochemical staining (IHC), cell cycle analysis, flow cytometry and fluorescence in situ hybridization (FISH). The sensitivity of PDX tumor to bortezomib and anlotinib monotherapy or in combination was investigated through cell proliferation, apoptosis and in vitro and in vivo experiments. The effects of anlotinib therapy on tumor blood vessel and cell apoptosis were analyzed by IHC, TUNEL staining and confocal fluorescence microscope.
RESULTS:MM PDX model was successfully established by subcutaneously inoculating primary MNCs. The morphologic features of tumor cells from MM PDX model were similar to those of mature plasma cells. MM PDX tumor cells positively expressed CD138 and CD38, which presented 1q21 amplification, deletion of Rb1 and IgH rearrangement, and had a lower proliferative activity than MM cell lines. in vitro, PDX, MM.1S and NCI-H929 cells were treated by bortezomib and anlotinib for 24 hours, respectively. Cell viability assay showed that the IC50 value of bortezomib were 5 716.486, 1.025 and 2.775 nmol/L, and IC50 value of anlotinib were 5 5107.337, 0.706 and 5.13 μmol/L, respectively. Anlotinib treatment increased the apoptosis of MM.1S cells (P < 0.01), but did not affect PDX tumor cells (P >0.05). in vivo, there was no significant difference in PDX tumor growth between bortezomib monotherapy group and control group (P >0.05), while both anlotinib monotherapy and anlotinib combined with bortezomib effectively inhibited PDX tumor growth (both P < 0.05). The vascular perfusion and vascular density of PDX tumor were decreased in anlotinib treatment group (both P < 0.01). The apoptotic cells in anlotinib treatment group were increased compared with those in control group (P < 0.05).
CONCLUSION:Bortezomib-resistant MM PDX model can be successfully established by subcutaneous inoculation of MNCs from MM patients in B-NDG mice. This PDX model, which retains the basic biological characteristics of MM cells, can be used to study the novel therapies.
