Modeling the dosage effect of oncogenes in leukemogenesis.

PURPOSE OF REVIEW: This review discusses the dosage effects of some oncogenes in leukemogenesis and compares various methods that model human hematologic malignancies in mice by introducing genetic lesions in a cell type-specific, time-controlled, and dosage-relevant manner. RECENT
FINDINGS: Recent evidence indicates that optimal dosage of cancer-related gene products plays an important role in the induction of mouse tumors that recapitulate their human counterparts.
SUMMARY: The mouse is a very valuable model system for experimentally dissecting the in vivo pathogenesis of cancer, for identifying pharmacological targets of cancer and for evaluating cancer therapies. In modeling human cancer, it has been shown that both the timing of introducing/activating oncogenic mutation(s) and the cell types into which the genetic lesion(s) is targeted are critical for cancer development. Recent studies also showed that efficient induction of relevant human leukemia in mice by certain oncogenes, such as PML/RARalpha and TEL/ABL, only occurred when they were expressed at a low level or close to pathophysiologically relevant level. These studies stress the importance of studying oncoprotein function at pathophysiologically relevant expression levels. Conditional gene expression systems are powerful tools for developing mouse models for human cancer by introducing genetic lesions in a cell type-specific, time-controlled and dosage-relevant manner. The bone marrow retroviral transduction and transplantation system can also mimic the cell and temporally specific origin of hematological malignancies by targeting oncogenes into sorted hematopoietic cells. This versatile approach is particularly powerful in structure-function analysis of oncogenes in vivo. However, overexpression of a transgene driven by retroviral vectors may alter the biological outcomes of the transgene in vivo. My colleagues and I have shown that generating vectors with modulated transgene expression can overcome this limitation of the retroviral transduction system in modeling human cancer in mice. Conditional gene expression and the modified retroviral transduction systems will be complimentary in studying human cancers in mice.