Humanized c-Myc Mouse

Abstract

BackgroundA 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 FindingsWe 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.ConclusionsThe 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.

MYC Dysregulates Mitosis, Revealing Cancer Vulnerabilities

“…Thus, we determined whether turning off expression of the human MYC transgene results in a corresponding increase in expression of the endogenous mouse MYC gene. Upon doxycycline withdrawal, endogenous murine MYC expression increased over time, detectable by qPCR and as a slightly upward shifted band by western blot that was shown to correspond to mouse MYC (Figures S1C and S1D) (Lehmann et al, 2012). We did not exceed three days incubation without doxycycline for the analysis of these cells to ensure low endogenous MYC expression.…”

Targeting c-MYC with T-Cells

“…To address whether a therapeutic window exists between anti-tumor immunity of c-MYC-specific T-cells and autoimmunity, we have generated a humanized c-MYC mouse in which the endogenous murine c-Myc gene is replaced by the human c-MYC gene. This mouse expresses the human c-MYC protein under the physiological control of the endogenous murine c-Myc promoter, is viable, and does not display an obvious phenotype [46]. This mouse will allow us to investigate whether tissue expression of the antigen causes autoimmunity when c-MYC specific T-cells are administered.…”

Zero-shot imputations across species are enabled through joint modeling of human and mouse epigenomics

“…Naturally, transcription and accessibility measure the same underlying phenomena in both species, but even histone modifications and proteins are known to play similar regulatory roles. For instance, in both species the histone modification H3K4me3 is enriched in active promoters [1,9], H3K27me3 is enriched in repressed promoters [19], and the transcription factor MYC is associated with cell growth [16,17].…”