白血病干细胞研究.ppt

白血病靶向治疗 娄世锋 Hematopoietic Stem Cell What Is a Hematopoietic Stem Cell? A hematopoietic stem cell is a cell isolated from the blood or bone marrow that can renew itself, can differentiate to a variety of specialized cells, can mobilize out of the bone marrow into circulating blood, and can undergo programmed cell death, called apoptosis—a process by which cells that are detrimental or unneeded self-destruct. 造血干细胞 stem cell 造血干细胞 Stem cell : Cell Markers Leukemia : a view in past Leukemic stem cell Leukemic stem cell AML-CFU in vitro SL-IC in vivo proliferation in SCID self-renewal first evidence of LSC Leukemic stem cell Properties of LSC Cell surface markers AML: CD34+, CD38–, CD71–, HLA–DR–, CD90–, CD117–, and CD123+ Guzman ML, Jordan CT. Considerations for targeting malignant stem cells in leukemia. Cancer Control. 2004;11:97–104 CML: CD34+, CD38– Holyoake TL, Jiang X, Drummond MW, Eaves AC, Eaves CJ. Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia. 2002;16:549–558. Properties of LSC self-renewal Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–737. Cell cycle status AML and CML stem cells maintain populations that are quiescent Guan Y, Gerhard B, Hogge DE. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML) Properties of LSC Unique molecular features AML cells upregulate the genes encoding IRF-1 and DAP kinase Guzman ML, Upchurch D, Grimes B, et al. Blood. 2001;97:2177–2179 High constitutive levels of NF- B activity Guzman ML, Neering SJ, Upchurch D, et al. Blood. 2001;98:2301–2307 CML cells are capable of autocrine interleukin (IL)-3 growth stimulation a