Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia

Blood. 2009 May 7;113(19):4702-10. doi: 10.1182/blood-2007-05-088724. Epub 2009 Feb 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / pathology*
  • Blast Crisis / genetics*
  • Blotting, Northern
  • Blotting, Southern
  • Blotting, Western
  • Bone Marrow Transplantation
  • Cell Proliferation
  • Colony-Forming Units Assay
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / physiology*
  • Female
  • Flow Cytometry
  • Fusion Proteins, bcr-abl / physiology*
  • Gene Expression Regulation, Leukemic*
  • Gene Rearrangement
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Retroviridae
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / physiology*
  • Zinc Fingers


  • DNA-Binding Proteins
  • Ebfaz protein, mouse
  • RNA, Messenger
  • RNA, Small Interfering
  • Transcription Factors
  • Fusion Proteins, bcr-abl