Genetic Identification of Hematopoietic Stem Cell Immortalization Genes.

Hematopoietic cancer is thought to arise from small populations of immortalized cancer stem cells that give rise to phenotypically diverse cells with less proliferative capacity. Cancer stem cell immortalization genes represent attractive drug targets for treating human cancer. We have found that immortalized cell lines can be generated in vitro following infection of mouse bone marrow cells with replication defective murine stem cell virus (MSCV). Immortalized myeloid progenitors can be selected in the presence of SCF plus IL-3 while immortalized multi-potent early hematopoietic progenitor cells can be selected with SCF and Flt3 ligand. So far, more than 80 such lines have been generated and they exhibit many properties attributed to cancer stem cells; they undergo unlimited self-renewal yet are able to give rise to phenotypically diverse cells with less proliferative capacity and in some cases they are leukemogenic in transplanted hosts. Immortalization often results from the insertional mutagenesis of human leukemia gene orthologues or genes that regulate them. Insertional mutagenesis by MSCV thus produces cells that share many properties attributed to cancer stem cells and may mark a subset of genes important for the immortalization of leukemic stem cells.