Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins

The MLL (Mixed Lineage Leukemia) gene is a common target for chromosomal tr anslocations associated with human acute leukemias. These translocations re sult in a gain of MLL function by generating novel chimeric proteins contai ning the amino-terminus of MLL fused in frame with one of 30 distinct partn er proteins. Structure/function studies using an in vitro myeloid progenito r immortalization assay have revealed that at least four nuclear partner pr oteins contribute transcriptional effector properties to MLL to produce a r ange of chimeric transcription factors with leukemogenic potential. Mouse m odels suggest that expression of an MLL fusion protein is necessary but not sufficient for leukemogenesis. Interestingly, whilst all MLL fusion protei ns tested so far phenocopy each other with respect to in vitro immortalizat ion, the latency period required for the onset of acute leukemia in vivo is variable and partner protein dependent. We discuss potential mechanisms th at may account for the ability of distinct MLL fusion proteins to promote s hort or long latency leukemogenesis.