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1、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 progra
2、mmed cell death,called apoptosisa process by which cells that are detrimental or unneeded self-destruct.,造血干细胞,造血干细胞,stem cell,This stem cell fuels chronic myelogenous leukemia,a type of cancer.,造血干细胞,CD150+(red),Stem cell:Cell Markers,Leukemia:a view in past,Leukemic stem cell,Only a small subset o
3、f cancer cells is capable of extensive proliferation Griffin JD et al,Blood(1986)68:1185,Leukemic stem cell,AML-CFU in vitroSL-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,HLADR,CD90,CD117,and CD123+
4、Guzman ML,Jordan CT.Considerations for targeting malignant stem cells in leukemia.Cancer Control.2004;11:97104 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.
5、2002;16:549558.,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;3:730737.Cell cycle status AML and CML stem cells maintain populations that are quiescent Guan Y,Gerhard B,Hogge D
6、E.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;97:21772179 Hi
7、gh constitutive levels of NF-B activity Guzman ML,Neering SJ,Upchurch D,et al.Blood.2001;98:23012307 CML cells are capable of autocrine interleukin(IL)-3 growth stimulation and activation of STAT5.Holyoake TL,Jiang X,Drummond MW,Eaves AC,Eaves CJ.Leukemia.2002;16:549558,Origin of LSC and Molecular P
8、athogenesis,hematopoietic stem cell(HSC)other types of early stem or progenitor cells,Origin of LSC and Molecular Pathogenesis,Cozzio A,Passegue E,Ayton PM,Karsunky H,Cleary ML,Weissman IL.Genes Dev.2003;17:30293035,Current Therapies and Future Directions,Our increasing understanding of LSC has allo
9、wed a reassessment of our clinical approach to AML and CML.,Current Therapies and Future Directions,Current Therapies and Future Directions,Targeting LSC surface molecules CD33 targeted approach IL-3 fusion to diphtheria toxin IL-3 fusion to PE,Current Therapies and Future Directions,PE,IL-3,Current
10、 Therapies and Future Directions,Inducing LSC-specific immunity T cell clones specific to minor histocompatibility antigens on LSC.Bonnet D,Warren EH,Greenberg PD,Dick JE,Riddell SR.CD8(+)minor histocompatibility antigen-specific cytotoxic T lymphocyte clones eliminate human acute myeloid leukemia s
11、tem cells.Proc Natl Acad Sci U S A.1999;96:86398644.,Current Therapies and Future Directions,Targeting LSC-specific molecular pathwaysinhibitors of the Flt3 transmembrane tyrosine kinase Proteasome inhibitor drugs inhibit NF-kB,normal HSC are relatively resistant to proteasome inhibition inhibit sig
12、naling in the PI3 kinase(PI3K)pathway,生物治疗,CIK Cell,生物治疗,CIK Cell,生物治疗,Dendritic Cells,DCCIK细胞治疗自体外周血造血干细胞移植后急性髓性白血病的临床研究,陈智超,4例患者已分别无病生存2年半、2年、2年、1年。,临床内科杂志2007年9月第24卷第9期 2007，Vol，24，No,自体CIK细胞辅助治疗非霍奇金淋巴瘤患者的临床观察,对6例非霍奇金淋巴瘤并且存在结外器官侵犯的患者，CIK细胞输注后可见患者体内CD3 CD56 细胞较前增加，影像学复查显示肿块缩小，治疗过程中主要出现畏寒、发热，未观察到其他
13、明显副作用,苏州大学附属第二医院血液科,中国血液流变学杂志2007；17(1),化疗联合自体细胞因子诱导杀伤细胞治疗急性白血病的临床观察江浩刘开彦 童春容江滨 陆道培,Current Therapies and Future Directions,Specific methods for targeting the CML stem cell may also relate to PI3K/Akt and NF-B signaling pathways,both of which are known to be active in CML cells.However,not all pathw
14、ays relevant to the survival of leukemic cells are necessary for survival of LSC.,Summary,A better understanding of human LSC is likely to provide exciting opportunities to develop improved leukemia therapies.Such approaches can be tailored to the unique biological properties of the LSC,while protec
15、ting the critical functions of normal HSC.As outlined above,several different approaches are emerging that show promise as more specific means to target the LSC population.In addition,powerful animal model systems have recently been described that will permit detailed analysis of LSC and the molecul
16、ar mechanisms that control their growth and survival.21 Such models also offer excellent systems in which novel experimental therapies can be evaluated.For the future,critical questions require further investigation:What types of stem or progenitor cells are capable of becoming LSC and what mutation
17、s can mediate their transformation?What mechanisms control the growth and survival of LSC?How do LSC respond to various therapeutic challenges?Does the origin of LSC affect their response to different therapies?And what type of intervention will induce LSC-specific cell death in vivo while sparing normal HSC?With the experimental tools currently in hand,each of these questions can be addressed and should lead to a variety of new therapeutic options for the treatment of myeloid leukemia.,
