MLL-ENL Causes a Reversible and myc-dependent Block of Myelomonocytic Cell Differentiation
2001
The translocation t(11;19) is a recurrent feature of a subgroup of acute
leukemiasoccurring 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.
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