第 第第第第 一 FROM Phospholipid Scramblase 1 (PLSCR1) TO Leukemic Cell Differentiati on 第 第第第第第第第 第 第第第第第第第第 Health Science Center , SIBS Zhao Ke-Wen
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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 , SIBSZhao Ke-Wen
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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
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细胞分化
造血干细胞
成熟血细胞
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白血病白血病(( LeukemiaLeukemia ))
第一作者论坛Specific translocation t(15;17)
Chromosome 1717
RAR Retinoic acid receptor-alpha
Chromosome 1515
PML promyelocytic leukemia
急性早幼粒细胞性白血病( APL )
-PMLRAR
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Acute Acute promyelocytic promyelocytic
LeukemiaLeukemia(APL)(APL)
PMLPMLPMLPML
RARRARRARRAR
PMLPMLPMLPML
RARRARRARRAR T(15;17)
AsAs22OO33 AsAs22OO33
ATRAATRA
All-trans-retinol
All-trans-retinoic acid
OH
COOH
13-cis-Retinoic acidCOOH
COOH
OH
CH2OH
9-cis-Retinoic acid
14-Hydroxy-4, 14-retro-retinol
(Adapted from Warrell et al, N Eng J Med, 1993)
APL is curable
Differentiation Therapy
Cancer Target Therapy
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cholinephospholipids : sphingomyelin ;phosphatidylcholine [PC]aminophospholipids : phosphatidylserine [PS] ; phosphatidylethanolamine[PE]
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ZHAO KW et al BLOOD2004
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• 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
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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
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PLSCR1 Leukemic Cell differentiation?
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ATRA could dose- and time-dependently
induce the expression of PLSCR1 (protein level, in NB4 cells)
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ATRA could time- and dose-dependently
induce the expression of PLSCR1 (mRNA level, in NB4 cells)
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ATRA PLSCR1NB4
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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
0C
D11
b+ c
ells
%G3PDH
c
bP
LS
CR
1/G
3PD
H
PLSCR1
-actin
NB4 NB4-LR1
0 1 2 3 4 days
0 1 2 3 4 days
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ATRA
PLSCR1NB4
LR1
PLSCR1
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PLSCR1Granulocytic
differentiation?
ATRA
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Increase in PLSCR1 expression is not limited to ATRA-induced
granulocytic differentiation
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PLSCR1Granulocytic
differentiation
ATRA
?
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PLSCR1 ?ATRA
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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
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PLSCR1 ?ATRA
PMA
PLSCR1 Leukemiccell differentiation ?
1
2
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PLSCR1
ATRA
PMAPKCδ
?
第一作者论坛 What is PKC?
cPKC(conventional PKC)
nPKC(novel PKC)
aPKC(Atypical PKC)
phorbolesters
Ca2+
phorbolesters
Ca2+
phorbolesters
Ca2+
phorbolesters
Ca2+
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PKC phosphorylation/activation is accompanied by increased PLSCR1 expression
Rottlerin: a PKC-specific inhibitor
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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
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Conclusion1:
PLSCR1 can be up-regulated by activation of PKC
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PLSCR1 Leukemiccell differentiation?
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Inhibition of PLSCR1 expression by siRNA partially blocks ATRA- and PMA-induced differentiation
c p r c p r c p rP2 P5
-actin
empty
PLSCR1
A
control PMA ATRA
cell
num
ber
CD11b
11.6%
3.0%
3.9%
71.2%
63.8%
49.6%
87.9%
62.7%
48.6%
B
P5
P
2
empt
y
10-6 M ATRA – +
empt
yP
5 iR
NA
C
c: control
p: PMA
r: ATRA
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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 acceptedfor publication in Blood.’
‘interesting, convincing ‘
第一作者论坛(Blood. 2004;104:3731-3738)
BLOOD, 1 DECEMBER 2004 VOLUME 104, NUMBER 12
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TO Share with you
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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
Linda B. Buck, Ph.D.
第一作者论坛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
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