Retroviral Insertional Mutagenesis in Murine Promonocytic Leukemias:c-myb and Mm/1

  • L. Wolff
  • R. Koller
  • J. Bies
  • V. Nazarov
  • B. Hoffman
  • A. Amanullah
  • M. Krall
  • B. Mock
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 211)


Studies have focused on two genetic loci, c-myb and Mml1, whose activation by retroviral insertional mutagenesis contribute to promonocytic leukemia in our acute monocytic leukemia (AMoL) model. Multiple mechanisms of activation of c-myb by retroviral insertional mutagenesis implicate both transcriptional deregulation and protein truncation in conversion of this proto-oncogene to an oncogene. Because transformation by c-Myb can be viewed as a block to differentiation our studies moved into two in vitro systems to evaluate effects of truncated forms of c-Myb on cytokine induced maturation of myeloid progenitors to the granulocyte and macrophage lineages. Deregulated expression of truncated and full length c-Myb did not result in maintenance of the myelomonocytic progenitor state but rather a block in differentiation at intermediate to late steps in the maturation processes of myelomonocytic cells. Our results argue that inhibition of differentiation is due to c-Myb’s ability to maintain the proliferative state of cells. Interestingly, the phenotype of continuously proliferating monocytic cells resembles that of the tumor cell phenotype. Recently we identified a new target of integration, Mml1, which is rearranged in ten promonocytic leukemias that do not have c-myb rearrangements. This locus which was mapped to chromosome 10 is presently being characterized.


Truncated Form Myeloid Progenitor Protein Truncation Acute Monocytic Leukemia Proviral Insertion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Shen-Ong GLC, Wolff, L (1987) Moloney murine leukemia virus-induced myeloid tumors in adult BALB/c mice: requirement of c-myb activation but lack of v-abl involvement J Virol 61:3721–3725PubMedGoogle Scholar
  2. 2.
    Wolff L, Mushinski JF, Shen-Ong GLC, Morse III HC (1988) A chronic inflammatory response: its role in supporting the development of c-myb and c-myc related promonocytic and monocyte tumors. J Immunol 141:681–689PubMedGoogle Scholar
  3. 3.
    Wolff L, Koller R, Davidson W (1991) Acute myeloid leukmia induction by amphotropic murine retrovirus (4070A): Clonal integrations involve c-myb in some but not all leukemias. J Virol 65:3607–3616PubMedGoogle Scholar
  4. 4.
    Mukhopadhyaya R, Wolff L (1992) New sites of proviral integration associated with muine promonocytic leukemias and evidence for alternate mode of c-myb activation. J Virol 66:6035–6044PubMedGoogle Scholar
  5. 5.
    Nazarov V, Wolff L (1995) Novel integration sites at the distal 3’ end of the c-myb locus in retrovirus-induced promonocytic leukemias. J Virol 69:3885–3888PubMedGoogle Scholar
  6. 6.
    Nason-Burchenal K, Wolff L (1993) Activation of c-myb is an early bone marrow event in a murine model for acute promonocytic leukemia. Proc Natl Acad Sci USA 90: 1619–1623PubMedCrossRefGoogle Scholar
  7. 7.
    Nazarov V, Hilbert D, Wolff L (1994) Susceptibility and resistence to Moloney murine leukemia virus-induCed promonocytic leukemia. Virology 205:479–485PubMedCrossRefGoogle Scholar
  8. 8.
    Mukhopadhyaya R, Richardson J, Nazarov V, Corbin A, Koller R, Sitbon M, Wolff L (1994) Different abilities of Friend murine leukmia virus (MuL V) and Moloney MuL V to induce promonocytic leukemia are due to determinants in both ψ-gag-PR and env regions. J Virol 68:5100–5107PubMedGoogle Scholar
  9. 9.
    Nason-Burchenal K, and Wolff L (1993) Involvement of the spleen in preleukemic development of a murine retrovirus-induced promonocytic leukemia Cancer Res 52:5317–5322Google Scholar
  10. 10.
    Belli B, Wolff L, Nazarov V, Fan H (1995) Proviral activation of the c-myb proto-oncogene in preleukemic mice infected neonatally with Moloney murine leukemia virus but not in resulting end-stage T -lymphomas J Virol, in pressGoogle Scholar
  11. 11.
    Graf T (1992) Myb: a transcriptional activator linking proliferation and differentiation in hematopoietic cells. Current Opinion in Genet Devel 2:249–255CrossRefGoogle Scholar
  12. 12.
    Introna M, Luchetti M, Castellano M, Arsura M, Golay J (1994) The myb oncogene family of transcription factors: potent regulators of hematopoietic cell proliferation and differentiation. Semin in Cancer Biol 5:113–124Google Scholar
  13. 13.
    Luscher B, Christenson E, Litchfield DW, Krebs EG, Eisenman RN (1990) Myb DNA binding is inbitited by phosphorylation at a site deleted during oncogenic activation Nature 344:517–522Google Scholar
  14. 14.
    Bousset K, Oelgeschlager MHH, Henriksson M, Schreek S, Burkhardt H, Litchfield DW, Luscher-Firzlaff JM, Luscher B (1994) Regulation of transcription factors c-Myc, Max, and CMyb by casein kinase II. Cell MolBiol Res 40:501–511Google Scholar
  15. 15.
    Dini P, Lipsick JS (1993) Oncogenic truncation of the first repeat of c-Myb decreases DNA binding in vitro and in vivo. Mol Cell Bioi 13:7334–7348Google Scholar
  16. 16.
    Sakura H, Kanei-Ishii C, Nakagoshi H, Gonda TJ, Ishii S (1989) Delineation of three fimctional domains of the transcriptional activator encoded by the c-myb protooncogene. Proc Natl Acad Sci USA 86:5758–5762PubMedCrossRefGoogle Scholar
  17. 17.
    Kalkbrenner F, Guehmann S, Moelling K (1990) Transcriptional activation by human c-myband v-myb genes. Oncogene 5:657–661PubMedGoogle Scholar
  18. 18.
    Dubendorff JW, Whittaker LJ, Eltman JT, Lipsick JS (1992) Carboxy-terminal elements of c-Myb negatively regulate transcriptional activation in cis and trans. Genes Dev 6:2524–2535PubMedCrossRefGoogle Scholar
  19. 19.
    Bies J, Mukhopadhyaya R, Pierce J, Wolff L (1995) Only late, nomnitotic stages of granulocyte differentiation in 32cl3 cells are blocked by ectopic expression of murine c-myb and its truncated forms. Cell Growth Differ 6: 59–68PubMedGoogle Scholar
  20. 20.
    Lord KA, Holffinan-Liebermann B, Liebermann D (1990) Dissection of the immediate early response of myeloid leukemic cells to terminal differentiation and growth inhibitory stimuli. Cell Growth Differ 1:637–645PubMedGoogle Scholar
  21. 21.
    Yanagisawa H, Nagasawa T, Kuramochi S, Abe T, Ikawa J, Todokoro K (1991) Constitutive expression of exogenous c-myb gene causes maturation block in monocyte-macrophage differentiation Biochim Biophysica Acta 1088:380–384Google Scholar
  22. 22.
    Burk O, Mink S, Ringwald M, Klempnauer K-H (1993) Synergisic activation of the chicken mimI gene by v-myb and CIEBP transcription factors. EMBO 12:2027–2038Google Scholar
  23. 23.
    Ness SA, Kowenz-Leutz E, Casini T, Graf T, Leutz A (1993) Myb and NF-M: combinatorial activators of myeloid gene in heterologous cell types. Genes Devel 7:749–759PubMedCrossRefGoogle Scholar
  24. 24.
    Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S, and Friedman AD (1994) PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEB2β/CBFβ proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells. Mol Cell Biol 14:5558–5568PubMedGoogle Scholar
  25. 25.
    Shapiro L (1995) Myb and ets proteins cooperate to transactivate an early myeloid gene. J Biol Chem 270:8763–8771PubMedGoogle Scholar
  26. 26.
    Hoffinan-Liebermann B, Liebermann DA (1991) Interleukin-6 and leukemia inhibitory factorinduced terminal differentiation of myeloid leukemia cells is blocked at an intermediate stage by constituitive c-myc. Mol Cell Biol 11:2375–2381Google Scholar
  27. 27.
    Selvakumaran D, Liebermann D, Hoffinan-Liebermann B (1993) Myeloblastic leukemia cells conditionally blocked by Myc-estrogen receptor chimera transgenes for terminal differentiation coupled to growth arrest and apoptosis. Blood 81:2257–2262PubMedGoogle Scholar
  28. 28.
    Evans JL, Moore TL, Kuehl WM, Bender T, Ting FP-Y (1990) Functional analysis of c-Myb protein in T -lymphocytic cell lines shows that it trans-activates the c-myc promoter. Mol Cell Biol 10:5747–5752PubMedGoogle Scholar
  29. 29.
    Zobel A, Kalkbrenner F, Guehmann S, Nawrath M Vordbrueggen G, Moelling K (1991) Interaction of the v-and cMyb proteins with regulatory sequences of the human c-myc gene. Oncogene 6: 1397–1407PubMedGoogle Scholar
  30. 30.
    Nakagoshi H, Kanei-Ishii C, Sawazaki T, Mizuguchi G, Ishii S (1992) Transcriptional activation of the c-myc gene by the c-myb and B-myb gene products. Oncogene 7:1233–1240PubMedGoogle Scholar
  31. 31.
    Cogswell JP, Cogswell PC, Kuehl WM, Cuddihy AM, Bender, TM, Engelke U, Marcu KB, Ting JP-Y (1993) Mechanism of c-myc regulation by c-Myb in different cell lineages. Mol Cell Biol 13:2858–2869PubMedGoogle Scholar
  32. 32.
    Selvakumaran D, Liebermann DA, Hoffman-Liebermann B (1992) Deregulated c-myb disrupts interleukin-6 or leukemia inhibitory factor-induced myeloid differentiation prior to c-myc: role in leukemogenesis. Mol Cell Bioi 12:2493–2500Google Scholar
  33. 33.
    Burk O, Klempnauer K-H (1991) Estrogen-dependent alterations in differentiation state of myeloid cells cause by a v-myb/estrogen receptor. EMBO 10:3713–3719Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • L. Wolff
    • 1
  • R. Koller
    • 1
  • J. Bies
    • 1
  • V. Nazarov
    • 1
  • B. Hoffman
    • 1
  • A. Amanullah
    • 1
  • M. Krall
    • 1
  • B. Mock
    • 2
  1. 1.Laboratory of GeneticsNational Cancer InstituteBethesdaUSA
  2. 2.Fels Institute for Cancer Research and Molecular BiologyTemple University School of MedicinePhiladelphiaUSA

Personalised recommendations