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Updated: May 19, 2026
Using the BLT Humanized Mouse as a Stem Cell based Gene Therapy Tumor Model
Published on: December 18, 2012
Humanized c-Myc mouse
Frank M Lehmann1, Samantha Feicht, Florian Helm
1Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, Munich, Germany.
Background:
A given tumor is usually dependent on the oncogene that is activated in the respective tumor entity. This phenomenon called oncogene addiction provides the rationale for attempts to target oncogene products in a therapeutic manner, be it by small molecules, by small interfering RNAs (siRNA) or by antigen-specific T cells. As the proto-oncogene product is required also for the function of normal cells, this raises the question whether there is a therapeutic window between the adverse effects of specific inhibitors or T cells to normal tissue that may limit their application, and their beneficial tumor-specific therapeutic action. To address this crucial question, suitable mouse strains need to be developed, that enable expression of the human proto-oncogene not only in tumor but also in normal cells. The aim of this work is to provide such a mouse strain for the human proto-oncogene product c-MYC.
Principal Findings:
We generated C57BL/6-derived embryonic stem cells that are transgenic for a humanized c-Myc gene and established a mouse strain (hc-Myc) that expresses human c-MYC instead of the murine ortholog. These transgenic animals harbor the humanized c-Myc gene integrated into the endogenous murine c-Myc locus. Despite the lack of the endogenous murine c-Myc gene, homozygous mice show a normal phenotype indicating that human c-MYC can replace its murine ortholog.
Conclusions:
The newly established hc-Myc mouse strain provides a model system to study in detail the adverse effects of therapies that target the human c-MYC protein. To mimic the clinical situation, hc-Myc mice may be cross-bred to mice that develop tumors due to overexpression of human c-MYC. With these double transgenic mice it will be possible to study simultaneously the therapeutic efficiency and adverse side effects of MYC-specific therapies in the same mouse.
Insights
Researchers developed a new mouse model expressing human c-MYC, which can replace the mouse version. This hc-Myc mouse strain is crucial for studying MYC-targeted cancer therapies and their side effects.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Tumors often rely on specific oncogenes, a concept known as oncogene addiction.
- Targeting oncogene products offers therapeutic strategies but faces challenges due to potential toxicity in normal cells.
- A therapeutic window is needed to balance anti-tumor effects with adverse effects on normal tissues.
Purpose of the Study:
- To develop a mouse model for studying therapies targeting the human c-MYC proto-oncogene.
- To create a system that allows expression of human c-MYC in both tumor and normal cells.
- To investigate the therapeutic window for c-MYC-targeted treatments.
Main Methods:
- Generated C57BL/6 embryonic stem cells engineered with a humanized c-Myc gene.
- Established a mouse strain (hc-Myc) where human c-MYC replaces the endogenous murine c-Myc.
- Integrated the humanized c-Myc gene into the murine c-Myc locus.
Main Results:
- The hc-Myc mouse strain successfully expresses human c-MYC in place of the murine ortholog.
- Homozygous hc-Myc mice exhibit a normal phenotype, indicating functional replacement by human c-MYC.
- Human c-MYC can fully substitute for murine c-MYC function in vivo.
Conclusions:
- The hc-Myc mouse strain serves as a valuable model for examining adverse effects of human c-MYC-targeting therapies.
- Cross-breeding hc-Myc mice with tumor-prone models will enable simultaneous evaluation of therapeutic efficacy and toxicity.
- This model facilitates comprehensive study of MYC-specific therapies in a clinically relevant context.
