Retroviral Insertional Mutagenesis in Murine Promonocytic Leukemias:c-myb and Mm/1
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.
KeywordsTruncated Form Myeloid Progenitor Protein Truncation Acute Monocytic Leukemia Proviral Insertion
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- 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.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
- 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.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.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.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
- 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.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
- 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
- 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
- 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.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