Blood, 1 January 2002, Vol. 99, No. 1, pp. 1-2
Putting oncogenes in their proper place
A prevalent oncogene created by chromosomal translocations in
acute myeloid leukemias is AML1-ETO, which is
commonly associated with leukemias displaying the FAB-M2 subtype. It
codes for a mutant form of AML1, the DNA binding component of a key
transcriptional regulatory complex that is essential for development
of the definitive hematopoietic system. Fusion with ETO in
leukemias drastically alters the transcriptional effector properties of
AML1, converting it into an obligate repressor, whereas normally it
functions predominantly as an activator. Despite these remarkable
insights into AML1-ETO molecular function, its primary effects on
hematopoietic cells that lead to initiation of leukemia are less clear.
Studies in several model systems have provided tantalizing hints of its
oncogenic role but also suggest that AML1-ETO may be relatively
cell-type specific in its subterfuge.
Mulloy and colleagues (page 15) have studied the effects of AML1-ETO on
the very cells thought to be targets for its nefarious actions in human
leukemias. Introduction of AML1-ETO into purified human hematopoietic
stem cells enhanced their expansion and self-renewal. Conversely, in
more mature progenitors, growth and clonogenic potential were
attenuated. The contrasting effects highlight the importance of
cellular milieu in determining the outcome of oncoprotein actions. Stem
cells dynamically counterbalance the opposing processes of
self-renewal and differentiation. AML1-ETO appears to
specifically corrupt this by stimulating self-renewal at the expense of
differentiation; it does not, however, seem to completely block
differentiation. Consequent increased stem cell cycling is likely to
provide a fertile setting for secondary mutations necessary for
progression to overt leukemia. The experimental approach of Mulloy and
colleagues should prove useful for identifying these secondary
collaborating events and for further dissection of the primary
transcriptional targets for AML1-ETO.
Michael L. Cleary
Stanford Medical
Center
