Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARalpha and NPM-RARalpha.
Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARalpha and one of four fusion partners: PML, PLZF, NPM, and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo, we generated transgenic mice with PLZF-RARalpha and NPM-RARalpha. PLZF-RARalpha transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage of life (within 3 months in five of six mice), whereas three NPM-RARalpha transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF-RARalpha transgenic mice, those from NPM-RARalpha transgenic mice could be induced to differentiate by all-trans-retinoic acid (ATRA). We also studied RARE binding properties and interactions between nuclear corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of SMRT from different receptors was observed at ATRA concentrations of 0.01 microM, 0.1 microM, and 1.0 microM for RARalpha-RXRalpha, NPM-RARalpha, and PML-RARalpha, respectively, but not observed for PLZF-RARalpha even in the presence of 10 microM ATRA. We also determined the expression of the tissue factor gene in transgenic mice, which was detected only in bone marrow cells of mice expressing the fusion genes. These data clearly establish the leukemogenic role of PLZF-RARalpha and NPM-RARalpha and the importance of fusion receptor/corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.
Cheng
G X
GX
Research Center for Transgenic Animals, College of Livestock and Veterinary, Yangzhou University, Yangzhou, People's Republic of China. chenggx@lvyuan.net.cn
Zhu
X H
XH
Men
X Q
XQ
Wang
L
L
Huang
Q H
QH
Jin
X L
XL
Xiong
S M
SM
Zhu
J
J
Guo
W M
WM
Chen
J Q
JQ
Xu
S F
SF
So
E
E
Chan
L C
LC
Waxman
S
S
Zelent
A
A
Chen
G Q
GQ
Dong
S
S
Liu
J X
JX
Chen
S J
SJ
D000818:Animals; D034961:Antigens, Nuclear; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D006128:Growth; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010641:Phenotype; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology; D016335:Zinc Fingers
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D006063:Chorionic Gonadotropin; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins; C489080:Numa1 protein, mouse; D015514:Oncogene Proteins, Fusion; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; C513267:Zbtb16 protein, mouse; C092037:ZBTB16 protein, human; D014212:Tretinoin