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FROM Phospholipid Scramblase 1 (PLSCR1) TO Leukemic Cell Differentiation 从 磷脂酰爬行酶 到 白血病细胞分化

FROM Phospholipid Scramblase 1 (PLSCR1) TO Leukemic Cell Differentiation 从 磷脂酰爬行酶 到 白血病细胞分化. Health Science Center ， SIBS Zhao Ke-Wen. 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. 成熟血细胞. 造血干细胞. 细胞分化. 白血病 （ Leukemia ）. Chromosome 17. RAR a: R etinoic a cid r eceptor-alpha. Chromosome 15.

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FROM Phospholipid Scramblase 1 (PLSCR1) TO Leukemic Cell Differentiation 从 磷脂酰爬行酶 到 白血病细胞分化

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  1. FROM Phospholipid Scramblase 1 (PLSCR1)TO Leukemic Cell Differentiation从磷脂酰爬行酶到白血病细胞分化 Health Science Center，SIBS Zhao Ke-Wen

  2. 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

  3. 成熟血细胞 造血干细胞 细胞分化

  4. 白血病 （Leukemia）

  5. Chromosome 17 RARa:Retinoic acid receptor-alpha Chromosome 15 PML:promyelocytic leukemia RARa -PML • Specific translocation t(15;17) 急性早幼粒细胞性白血病（APL）

  6. (Adapted from Warrell et al, N Eng J Med, 1993) OH All-trans-retinol ATRA COOH COOH 9-cis-Retinoic acid All-trans-retinoic acid Acute promyelocytic Leukemia (APL) CH2OH PML RARa PML RARa PML RARa PML RARa OH T(15;17) COOH 13-cis-Retinoic acid 14-Hydroxy-4, 14-retro-retinol Differentiation Therapy As2O3 Cancer Target Therapy • APL is curable

  7. cholinephospholipids : sphingomyelin ;phosphatidylcholine [PC] aminophospholipids : phosphatidylserine [PS] ; phosphatidylethanolamine[PE]

  8. ZHAO KW et al BLOOD2004

  9. In mice • Normal hemostasis but defective hematopoietic response in plscr1-/-mice ; • MmTRA1a, a truncated form of murine PLSCR1 was identified in a monocytic leukemia cell line

  10. 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

  11. Leukemic Cell differentiation PLSCR1 ?

  12. ATRA could dose-and time-dependently induce the expression of PLSCR1 (protein level, in NB4 cells)

  13. ATRA could time-and dose-dependently induce the expression of PLSCR1 (mRNA level, in NB4 cells)

  14. ATRA NB4 PLSCR1

  15. a 100 75 50 25 0 CD11b+ cells% 0 1 2 3 4 days b G3PDH 4 2 0 PLSCR1 /G3PDH PLSCR1 0 1 2 3 4 days c PLSCR1 -actin 2 1 0 0 1 2 3 4 days NB4-LR1 NB4 ATRA could not induce PLSCR1 expression in ATRA-resistant NB4-derived NB4-LR1 cells

  16. NB4 PLSCR1 ATRA LR1 PLSCR1

  17. ATRA Granulocytic differentiation ? PLSCR1

  18. Increase in PLSCR1 expression is not limited to ATRA-induced granulocyticdifferentiation

  19. ATRA ? Granulocytic differentiation PLSCR1

  20. ATRA ? PLSCR1

  21. 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

  22. PMA ? PLSCR1 1 ATRA Leukemic cell differentiation ? 2 PLSCR1

  23. PMA PKCδ PLSCR1 ? ATRA

  24. What is PKC? phorbol esters Ca2+ cPKC (conventional PKC) a b  phorbol esters   phorbol esters Ca2+ nPKC (novel PKC)    Ca2+ phorbol esters Ca2+ aPKC (Atypical PKC)  

  25. Rottlerin: a PKC-specific inhibitor PKC  phosphorylation/activation is accompanied by increased PLSCR1 expression

  26. CF : catalytic fragment of PKC  A G3PDH PLSCR1 1 0.5 0 CON CF1.5 B PLSCR1 -actin CON N1 CF1.0 CF1.5 Ectopic expression of the catalytic fragment of PKC (CF ) can induce expression of PLSCR1

  27. Conclusion1:PLSCR1 can be up-regulated by activation of PKC

  28. ? Leukemic cell differentiation PLSCR1

  29. A empty P5 P2 c p r c p r c p r PLSCR1 -actin B C 10-6 M ATRA – + control PMA ATRA 11.6% 3.0% 3.9% 87.9% 62.7% 48.6% 71.2% 63.8% 49.6% empty P5 P2 empty P5 iRNA cell number CD11b c: control p: PMA r: ATRA Inhibition of PLSCR1 expression by siRNA partially blocks ATRA- and PMA-induced differentiation

  30. Conclusion2: PLSCR1 involves in leukemic cell differentiation

  31. 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 acceptedfor publication in Blood.’ • ‘interesting,convincing ‘

  32. (Blood. 2004;104:3731-3738) BLOOD, 1 DECEMBER 2004 VOLUME 104, NUMBER 12

  33. TO Share with you

  34. 团队精神 • 充分的准备 • 主动地交流 • 实干+巧干 规范实验+归纳总结 • 正确地对待挫折和失败

  35. acknowledgements • SIBS, AC • Guo-Qiang Chen; • Qian Zhao; • Xi Li; • Dong Li; • Ying Huang; • Ci-Xiang Zhou; • Jing Zhang; • Zhen-Gang Peng; • Shi-Hua Liao • Mei-Yi Zhou; • Meng Zhao

  36. THANKS!

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