Targeting eradication of malignant cells derived from human bone marrow mesenchymal stromal cells

Area of Science:

• Stem cell biology
• Cancer research
• Gene therapy

Background:

• Human bone marrow mesenchymal stromal cells (hBMSC) can undergo malignant transformation.
• The low frequency of hBMSC malignant transformation hinders the development of preventative strategies.
• A model is needed to study and eradicate hBMSC-derived malignant cells.

Purpose of the Study:

• To establish a model for the targeted eradication of malignant cells derived from hBMSC.
• To investigate the efficacy of a suicide gene system controlled by a modified promoter in eliminating transformed hBMSC.

Main Methods:

• Engineered a gene construct with a modified human telomerase (hTERT) promoter, c-Myc and MZF-2 binding elements, and the E. coli cytosine deaminase (CD) gene.
• Transduced hBMSC with the gene construct via lentiviral vectors.
• Induced malignant transformation using Benzo(a)pyrene Diol Epoxide (BPDE) and selected for malignant cells using n-phosphonacelyl-L-aspartic acid (PALA).
• Administered 5-fluorocytosine (5-FC) to test the efficacy of the CD/5-FC suicide system.

Main Results:

• Successfully generated PALA-resistant malignant cells from hBMSC.
• The modified hTERT promoter showed enhanced activity in malignant cells compared to normal hBMSC.
• Malignant cells expressing cytosine deaminase (CD) were effectively eliminated by 5-FC administration.

Conclusions:

• A novel model for generating and eradicating hBMSC-derived malignant cells was established.
• The modified hTERT promoter effectively drives suicide gene expression in malignant hBMSC.
• This gene therapy approach offers a method for the targeted elimination of malignant cells originating from hBMSC.