title: Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia.
abstract: 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.
authors.affiliation: Department of Developmental Biology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Norimasa
authors.initials: N
authors.lastname: Yamasaki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kanno
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Komeno
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitaura
authors.forename: Zen-ichiro
authors.initials: Z
authors.lastname: Honda
authors.forename: Søren
authors.initials: S
authors.lastname: Warming
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
mesh_terms: 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
chemical_list: D004268:DNA-Binding Proteins; C484557:Ebfaz protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016044:Fusion Proteins, bcr-abl