Retroviral insertional mutagenesis in murine promonocytic leukemias: c-myb and Mml1.
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.
Wolff
L
L
Laboratory of Genetics, National Cancer Institute, Bethesda, MD 20892-4255, USA.
Koller
R
R
Bies
J
J
Nazarov
V
V
Hoffman
B
B
Amanullah
A
A
Krall
M
M
Mock
B
B
D000818:Animals; D002454:Cell Differentiation; D006098:Granulocytes / Q000502:physiology; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics*; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics* / Q000821:virology; D008264:Macrophages / Q000502:physiology; D016254:Mutagenesis, Insertional; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016662:Virus Integration
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc