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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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