MLL (HRX) fusion proteins in leukemogenesis
Alterations of the MLL gene (also called ALL-1 or HRX) define a subset of acute leukemias
with distinctive
clinical and biological features. Our cloning
of the MLL gene showed that the encoded protein shares structural similarities
with Drosophila trithorax, which genetic studies implicate in the maintenance
of Hox gene expression. Over 20 different partner proteins are fused
with MLL as a result of chromosomal translocations in leukemias.
Using retroviral-mediated gene transfer, we have shown that several MLL
fusion proteins immortalize
primary myeloid progenitors in vitro. Cells expressing these
fusion proteins cause fatal myeloid leukemias in mice. Our studies
indicate that leukemic translocations affecting MLL result in a gain
of function dependent on transcriptional effector domains of the fusion
partner that are critical for transformation. We are investigating
whether select Hox genes are subordinate to MLL and required for its oncogenic
effects. Other interests also focus on the molecular mechanisms by
which MLL maintains Hox gene expression and identification of other MLL
subordinate genes that contribute to leukemogenesis.
