论文部分内容阅读
Leukemia,like many other cancers,is thought to arise from a small population of stem cells that have the capacity to self-renewal extensively and to initiate,sustain or regenerate the disease.Elimination of the leukemia stem cells(LSCs) will likely be essential,and probably sufficient,for curing this disease.Recent studies have shown that LSCs can be derived from early hematopoietic progenitors as well as more differentiated derivatives;the key feature being these cells have acquired an increased proliferative capacity and the ability to self-renew extensively.Genes that make this possible are attractive drug targets for treating leukemia.In our laboratory we have developed a novel in vitro genetic screen that uses retroviral insertional mutagenesis as a tool for identifying genes that are able to convert both normal hematopoietic progenitors and committed myeloid progenitor cells into cells that resemble LSCs.Interestingly,the genes identified in this screen are either known human leukemia genes or genes thought to regulate them?Recently,insertional mutations in these same genes were identified in the blood of X-linked granulomatous disease patients following retroviral gene therapy and likely reinforced the therapeutic efficacy in this trial.The insertional mutations were associated with a 3-4 expansion in the myeloid compartment of gene-corrected patients,indicating that mutations in these genes also have an effect on the self-renewal of human hematopoietic cells.Currently,we are determining whether this screen can be extended to other cells types(i.e.,epithelial cells) and whether we can use this information to develop better methods for killing LSCs.
Leukemia, like many other cancers, is thought to arise from a small population of stem cells that have the capacity to self-renewal extensively and of to sustain or regenerate the disease. Elimination of the leukemia stem cells (LSCs) will likely be essential , and probably sufficient, for curing this disease. Recent studies have shown that LSCs can be derived from early hematopoietic progenitors as well as more differentiated derivatives; the key feature are these cells have acquired an increased proliferative capacity and the ability to self-renew extensively .Genes that make this possible are attractive drug targets for treating leukemia. In our laboratory we have developed a novel in vitro genetic screen that uses retroviral insertional mutagenesis as a tool for identifying genes that are able to convert both normal hematopoietic progenitors and committed myeloid progenitor cells into cells that resemble LSCs.Interestingly, the genes identified in this screen are either known human leu Recently, insertional mutations in these same genes were identified in the blood of X-linked granulomatous disease patients following retroviral gene therapy and likely reinforced the therapeutic efficacy in this trial. insertional mutations were associated with a 3-4 expansion in the myeloid compartment of gene-corrected patients, indicating that mutations in these genes also have an effect on the self-renewal of human hematopoietic cells. Current, we are determining whether this screen can be extended to other cells types ie, epithelial cells) and whether we can use this information to develop better methods for killing LSCs.