Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia.
Chronic myelogenous leukemia (CML) is a hematopoietic disorder originating from p210BCR/ABL-transformed stem cells, which begins as indolent chronic phase (CP) but progresses into fatal blast crisis (BC). To investigate molecular mechanism(s) underlying disease evolution, CML-exhibiting p210BCR/ABL transgenic mice were crossed with BXH2 mice that transmit a replication-competent retrovirus. Whereas nontransgenic mice in the BXH2 background exclusively developed acute myeloid leukemia, p210BCR/ABL transgenic littermates developed nonmyeloid leukemias, in which inverse polymerase chain reaction detected 2 common viral integration sites (CISs). Interestingly, one CIS was transgene's own promoter, which up-regulated p210BCR/ABL expression. The other was the 5' noncoding region of a transcription factor, Zfp423, which induced aberrant Zfp423 expression. The cooperative activities of Zfp423 and p210BCR/ABL were demonstrated as follows: (1) introduction of Zfp423 in p210BCR/ABL transgenic bone marrow (BM) cells increased colony-forming ability, (2) suppression of ZNF423 (human homologue of Zfp423) in ZNF423-expressing, p210BCR/ABL-positive hematopoietic cells retarded cell growth, (3) mice that received a transplant of BM cells transduced with Zfp423 and p210BCR/ABL developed acute leukemia, and (4) expression of ZNF423 was found in human BCR/ABL-positive cell lines and CML BC samples. These results demonstrate that enhanced expression of p210BCR/ABL and deregulated expression of Zfp423/ZNF423 contribute to CML BC.
Miyazaki
Kazuko
K
Department of Developmental Biology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Yamasaki
Norimasa
N
Oda
Hideaki
H
Kuwata
Takeshi
T
Kanno
Yohei
Y
Miyazaki
Masaki
M
Komeno
Yukiko
Y
Kitaura
Jiro
J
Honda
Zen-ichiro
Z
Warming
Søren
S
Jenkins
Nancy A
NA
Copeland
Neal G
NG
Kitamura
Toshio
T
Nakamura
Takuro
T
Honda
Hiroaki
H
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D001752:Blast Crisis / Q000235:genetics*; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C484557:Ebfaz protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016044:Fusion Proteins, bcr-abl