The
translocation t(11;19) is a recurrent feature of a subgroup of acute
leukemias occurring in infants. This event fuses the genes MLL and ENL and creates the leukemogenic
oncoprotein MLL-ENL. We studied the effect of
retroviral MLL-ENL expression in primary
mouse hematopoietic cells and show here that MLL-ENL requires the
oncoprotein Myc to establish a reversible differentiation arrest of a myelomonocytic precursor population. MLL-ENL-transduced cells proliferated as immature
myeloid cells in the presence of
interleukin 3. The addition of
granulocyte colony-stimulating factor reversed the maturation block set by MLL-ENL and induced the development of mature
granulocytes and
macrophages accompanied by growth arrest.
Gene expression analysis indicated a down-regulation of the
proto-oncogene c-myc and of several c-myc target genes during
granulocyte colony-stimulating factor-mediated differentiation. The role of c-myc in the MLL-ENL transformation pathway was tested by modulating the effective
Myc protein concentrations in MLL-ENL transduced cells.
Cotransduction of dominant-negative
Myc neutralized the MLL-ENL effect and precluded transformation. In contrast, constitutive expression of
Myc cooperated with MLL-ENL and caused the transformation of a cell population with an irreversible maturation arrest.
