Differentiation primary response genes and proto-oncogenes as positive and negative regulators of terminal hematopoietic cell differentiation.
By genetically manipulating hematopoietic cells of the myeloid lineage, including both normal cells and differentiation inducible leukemic cell lines, evidence was obtained to indicate that myeloid differentiation primary response (MyD) genes and proto-oncogenes, which are known to control cell growth, function as positive and negative regulators of terminal hematopoietic cell differentiation, which is associated with inhibition of cell growth, and, ultimately programmed cell death (apoptosis). Interferon regulatory factor-1 (IRF-1), an MyD gene induced by Interleukin 6 (IL-6) or Leukemia Inhibitory factor (LIF), plays a role in growth inhibition associated with terminal differentiation. Leucine zipper transcription factors of the fos/jun family, also identified as MyD genes, function as positive regulators of hematopoietic cell differentiation, increasing the propensity of myeloblastic leukemia cells to be induced for differentiation in vitro, and reducing the aggressiveness of their leukemic phenotype in vivo. The zinc finger transcription factor EGR-1, an MyD gene specifically induced upon macrophage differentiation, was shown to be essential for and to restrict differentiation along the macrophage lineage. Finally, evidence has been accumulating to indicate that the novel MyD genes--MyD116, MyD118 and gadd45 (a member in the MyD118 gene family)--play a role in growth arrest and apoptosis of hematopoietic cells, as well as other cell types. The proto-oncogenes c-myc and c-myb, known to regulate cellular growth, were shown to function as negative regulators of terminal differentiation. Both c-myc and c-myb are normally expressed in proliferating myeloblasts and suppressed following induction of differentiation. Deregulated and continuous expression of c-myc was shown to block terminal myeloid differentiation at an intermediate stage in the progression from immature blasts to mature macrophages, whereas deregulated and continuous expression of c-myb blocked the terminal differentiation program at the immature myeloblast stage. By manipulating myc function in conditional (differentiation inducible) mutant myeloblastic leukemia cell lines, expressing a chimeric mycer transgene, it was shown that there is a window during myeloid differentiation, after the addition of the differentiation inducer, when the terminal differentiation program switches from being dependent on c-myc suppression to becoming c-myc suppression independent, and where activation of c-myc has no apparent effect on mature macrophages. These myeloblastic leukemia cell lines provide a powerful tool to increase our understanding of the role of c-myc in normal hematopoiesis and in leukemogenesis, while also providing a strategy to clone myc target genes.(ABSTRACT TRUNCATED AT 250 WORDS)
Fels Institute for Cancer Research and Molecular Biology, Temple University, School of Medicine, Philadelphia, Pennsylvania 19140.
D A
DA
Liebermann
B
B
Hoffman
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D000943:Antigens, Differentiation; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics*; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D016259:Genes, myc; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology; D050856:Interferon Regulatory Factor-1; D047908:Intracellular Signaling Peptides and Proteins; D016350:Leucine Zippers / Q000502:physiology; D007938:Leukemia / Q000235:genetics / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D009363:Neoplasm Proteins; D014411:Neoplastic Stem Cells / Q000473:pathology; D009857:Oncogenes; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D054645:Protein Phosphatase 1; D011506:Proteins / Q000235:genetics / Q000502:physiology; D011519:Proto-Oncogenes; D011971:Receptors, Immunologic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D050856:Interferon Regulatory Factor-1; D047908:Intracellular Signaling Peptides and Proteins; D053594:Myeloid Differentiation Factor 88; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D054645:Protein Phosphatase 1; D011506:Proteins; D011971:Receptors, Immunologic; D014157:Transcription Factors; D000097642:GADD45 Proteins; C497325:EGR1 protein, human; C486109:Egr1 protein, mouse; C086470:GADD45B protein, human; C490125:Gadd45b protein, mouse; C494257:IRF1 protein, human; C494258:Irf1 protein, mouse; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C087519:PPP1R15A protein, human; C513256:Ppp1r15a protein, mouse