Leukemia suppressor function of Egr-1 is dependent on transforming oncogene.
We have shown that deregulated expression of either c-Myb or E2F-1 blocks terminal differentiation of M1 myeloid leukemia cells at the blast stage, whereas deregulated c-Myc blocks differentiation at the intermediate stage. Each of these oncogenes potentiates M1 leukemia in vivo. The zinc-finger transcription factor Egr-1 abrogates the block in M1 terminal differentiation imparted by oncogenic c-Myc or E2F-1, suppressing their leukemia-promoting function in nude mice. In this study, we asked whether Egr-1 also abrogates the block in terminal differentiation and suppresses leukemia imparted by deregulated c-Myb. Interestingly, the ectopic expression of Egr-1 in M1 cells expressing deregulated c-Myb only partially abrogated the block in terminal differentiation and did not suppress the leukemic phenotype. Two important implications from these data are that the leukemia suppressor function of Egr-1 is not directly related to how early the transforming oncogene blocks the differentiation program and that the tumor suppressor function of Egr-1 is dependent on the specific oncogene. Egr-1 is dominant to c-Myc- and E2F-1-, but not to c-Myb-, driven leukemia. These findings extend the notion that the molecular nature of genetic lesions responsible for leukemia determines the effectiveness of any given tumor suppressor.
Gibbs
J D
JD
Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA 19140, USA.
Liebermann
D A
DA
Hoffman
B
B
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D020570:Genes, myb / Q000502:physiology*; D016259:Genes, myc / Q000502:physiology*; D015850:Interleukin-6 / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D010587:Phagocytosis; D010770:Phosphotransferases / Q000032:analysis / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C492236:Cdk5r1 protein, mouse; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D015850:Interleukin-6; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010770:Phosphotransferases