Analysis of Leukemogenic Gene Products in Hematopoietic Progenitor Cells

摘要: One major limitation in the development of effective and targeted cancer therapies is incomplete understanding molecular mechanisms driving malignant cell growth resistance residual cancer stem cells to standard therapies, such as chemotherapy radiation. Consequently, numerous attempts have been made elucidate circuits initiating perpetuating transformation. Among different entities, leukemias harbor only a few mutations therefore represent good model system for study oncogenesis. The cloning subsequent analysis leukemia-associated gene products strongly facilitated their biological function appropriate systems. In early experiments, oncogenes were ectopically expressed fibroblasts, type which not optimal modeling leukemia initiation progression. Later, separation methods murine human hematopoietic precursor cells allowed isolation specific target cells, large quantities with high population purity (Belvedere et al., 1999). Together utilization retroviral expression vectors, enable stable integration transgene choice, these procedures significant methodological improvement approaches tissue. With technologies hand, genetic lesions can be better modeled compartment. By performing biology experiments tumor sample deep sequencing it became clear that both solid tumors hematological malignancies depend on multiple oncogenic alterations ultimately result cellular transformation (Hanahan & Weinberg, 2000, 2011; Kinzler Vogelstein, 1996). Additionally, overall number mutated genes was found higher than leukemias. These observations resulted formulation multi-hit tumorigenesis. Initiating induce expansion survival, thereby allowing occurrence additional progression later stages this process are characterized by uncontrolled proliferation overgrowth healthy compartment metastasis, case tumors. This has well described colon Kenneth W. Bert Vogelstein (Kinzler