医学课件从磷脂酰爬行酶到白血病细胞分化

第一作者论坛 FROM Phospholipid Scramblase 1 (PLSCR1) TO Leukemic Cell Differentiation 从从 磷脂酰爬行酶 到到 白血病细胞分化 Health Science Center， SIBS Zhao Ke-Wen 第一作者论坛 恶性肿瘤是威胁人类健康的主要杀手。 在我国，白血病占恶性肿瘤的第 7位 第一作者论坛 细胞分化 造血干细胞 成 熟 血 细 胞 第一作者论坛 白血病白血病 （ Leukemia） 第一作者论坛vSpecific translocation t(15;17) Chromosome 17 RARa: Retinoic acid receptor-alpha Chromosome 15 PML: promyelocytic leukemia 急性早幼粒细胞性白血病（ APL） -PMLRARa 第一作者论坛 Acute promyelocytic Leukemia (APL) PML PML RARa RARa T(15;17) As2O3 ATRA All-trans-retinol All-trans-retinoic acid OH COOH 13-cis-Retinoic acid COOH COOH OH CH2OH 9-cis-Retinoic acid 14-Hydroxy-4, 14-retro-retinol (Adapted from Warrell et al, N Eng J Med, 1993) vAPL is curable Differentiation Therapy Cancer Target Therapy 第一作者论坛 cholinephospholipids : sphingomyelin ;phosphatidylcholine PC aminophospholipids : phosphatidylserine PS ; phosphatidylethanolaminePE 第一作者论坛 第一作者论坛 第一作者论坛 ZHAO KW et al BLOOD2004 第一作者论坛 Normal hemostasis but defective hematopoietic response in plscr1-/-mice ; MmTRA1a, a truncated form of murine PLSCR1 was identified in a monocytic leukemia cell line In mice 第一作者论坛 第一作者论坛 第一作者论坛 In human AML patients with higher levels of PLSCR1 mRNA were associated with significantly longer overall survival, particularly in patients of the AML-M4 subtype 第一作者论坛 PLSCR1 Leukemic Cell differentiation? 第一作者论坛 ATRA could dose- and time-dependently induce the expression of PLSCR1 (protein level, in NB4 cells) 第一作者论坛 ATRA could time- and dose-dependently induce the expression of PLSCR1 (mRNA level, in NB4 cells) 第一作者论坛 ATRA PLSCR1NB4 第一作者论坛 ATRA could not induce PLSCR1 expression in ATRA-resistant NB4-derived NB4-LR1 cells PLSCR1 a 2 1 0 0 1 2 3 4 days 4 2 0 100 75 50 25 0 CD11b + cells% G3PDH c b PLSCR1/G3PDH PLSCR1 -actin NB4 NB4-LR1 0 1 2 3 4 days 0 1 2 3 4 days 第一作者论坛 ATRA PLSCR1 NB4 LR1 PLSCR1 第一作者论坛 PLSCR1 Granulocytic differentiation? ATRA 第一作者论坛 Increase in PLSCR1 expression is not limited to ATRA-induced granulocytic differentiation 第一作者论坛 PLSCR1 Granulocytic differentiation ATRA? 第一作者论坛 PLSCR1 ?ATRA 第一作者论坛 DMSO:dimethyl sulfoxide SB: sodium butyrate a histone deacetylase inhibitor PMA: phorbol 12-myristate 13-acetate VD3:Vitamin D3 C: PLSCR1 expression induced by ATRA and PMA was not restricted to leukemic cells 第一作者论坛 PLSCR1 ? ATRA PMA PLSCR1 Leukemiccell differentiation? 1 2 第一作者论坛 第一作者论坛 PLSCR1 ATRA PMA PKC? 第一作者论坛 What is PKC? cPKC (conventional PKC) nPKC (novel PKC) aPKC (Atypical PKC) phorbol esters Ca2+ phorbol esters Ca2+ phorbol esters Ca2+ phorbol esters Ca2+ a 第一作者论坛 PKC phosphorylation/activation is accompanied by increased PLSCR1 expression Rottlerin: a PKC-specific inhibitor 第一作者论坛 Ectopic expression of the catalytic fragment of PKC (CF ) can induce expression of PLSCR1 CON CF1.5 1 0.5 0 B PLSCR1 -actin CON N1 CF1.0 CF1.5 CF : catalytic fragment of PKC G3PDH PLSCR1 A 第一作者论坛 Conclusion1: PLSCR1 can be up-regulated by activation of PKC 第一作者论坛 PLSCR1 Leukemiccell differentiation? 第一作者论坛 Inhibition of PLSCR1 expression by siRNA partially blocks ATRA- and PMA-induced differentiation c p r c p r c p r P2 P5 -actin empty PLSCR1 A control PMA ATRA cell number CD11b 11.6% 3.0% 3.9% 71.2% 63.8% 49.6% 87.9% 62.7% 48.6% B P5 P2 empty 10-6 M ATRA + empty P5 iRNA C c: control p: PMA r: ATRA 第一作者论坛 Conclusion2: PLSCR1 involves in leukemic cell differentiation 第一作者论坛 2004-4-28 submission to BLOOD 2004-5-26 BLOOD response : I am happy to report that the paper was favorably received and, provided an appropriate revision is prepared, can be accepted for publication in Blood. interesting, convincing 第一作者论坛 (Blood. 2004;104:3731-3738) BLOOD, 1 DECEMBER 2004 VOLUME 104, NUMBER 12 第一作者论坛 TO Share with you 第一作者论坛 v团队精神 v充分的准备 v主动地交流 v实干 +巧干 规范实验 +归纳总结 v正确地对待挫折和失