Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice

The MLL-ELL fusion gene results from the translocation t(11;19)(q23;p13.1) that is associated with de novo and therapy-related acute myeloid leukemia. To study its transforming properties, we retrovirally transduced primary m urine hematopoietic progenitors and assessed their growth properties both i n vitro and in vivo. MLL-ELL increased the proliferation of myeloid colony- forming cells in methylcellulose cultures upon serial replating, whereas ov erexpression of ELL alone had no effect. We reconstituted lethally irradiat ed congenic mice with bone marrow progenitors transduced with MLL-ELL or th e control MIE vector encoding the enhanced green fluorescent protein. When the peripheral blood of the mice was analyzed 11-13 weeks postreconstitutio n, we found that the engraftment of the MLL-ELL-transduced cells was superi or to that of the MIE controls. At this time point, the contribution of the donor cells was normally distributed among the myeloid and nonmyeloid comp artments. Although all of the MIE animals (n = 10) remained healthy for mor e than a year, all of the MLL-ELL mice (n = 20) succumbed to monoclonal or pauciclonal acute myeloid leukemias within 100-200 days. The leukemic cells were readily transplantable to secondary recipients and could be establish ed as immortalized cell lines in liquid cultures. These studies demonstrate the enhancing effect of MLL-ELL on the proliferative potential of myeloid progenitors as well as its causal role in the genesis of acute myeloid leuk emias.