In Vivo Generation of Leukemic Stem Cells by HSC Targeting by Transgenesis

Leukemia is a clonal malignant disease originated in a single cell and characterized by the accumulation of abnormal lymphoid cells. The nature of the leukemic stem cell (LSC) has been a subject of continuing discussion, given the fact that human disease is diagnosed at late stages and cannot be monitored during its natural evolution from its cell of origin. Animal models provide a means to determine the leukemic initiating cell and the causes of malignancy, and to develop new treatments. Recent findings in mice have shown that cancer stem cells can initially arise through a reprogramming-like mechanism when the oncogene expression is targeted to the mouse stem cell compartment (Garcia-Ramirez et al., EMBO J 37(14):298783, 2018; Martin-Lorenzo et al., Cancer Res 78 (10):2669-2679, 2018; Perez-Caro et al., EMBO J 28(1):8-20, 2009; Rodriguez-Hernandez et al., Cancer Res 77(16):4365-4377, 2017). If leukemia arises through reprogramming processes, then perhaps many of the oncogenes that initiate tumor formation might be dispensable for tumor progression and maintenance. Leukemia will be modeled in the mice only if we are able to target the right cancer-initiating cell with a precise given oncogene. In the last years, some examples have already started to appear in the literature showing that targeting oncogene expression to the stem cell compartment in model mice might be the correct way of reproducing the genotype-phenotype correlations found in human leukemias (Garcia-Ramirez et al., EMBO J 37(14):298783, 2018; Martin-Lorenzo et al., Cancer Res 78 (10):2669-2679, 2018; Perez-Caro et al., EMBO J 28(1):8-20, 2009; Rodriguez-Hernandez et al., Cancer Res 77(16):4365-4377, 2017). This chapter addresses how to generate LSCs by transgenesis in a way that makes the resulting animal models valuable tools to reproduce and understand leukemogenesis, and for the development of therapeutic applications like drug discovery or biomarker identification.