Abstract
The MLL (Mixed-Lineage Leukemia) gene was originally identified at chromosomal 11q23 translocations developing acute leukemia, which occurs at high frequency in infantile and secondary leukemia. As a consequence of rearrangements of MLL, MLL is fused with one of more than 50 different partner genes to yield a diverse collection of MLL fusion oncoproteins. Normal MLL protein assembles into a chromatin-modifying transcriptional regulatory supercomplex to regulate epigenetic pathways including methylation of histone H3 lysine 4, and plays a nonredundant and essential role in definitive hematopoiesis through maintenance of appropriate upregulation of HOX genes associated with methylation of histone H3 at their locus. Meanwhile, oncogenic MLL fusion protein, where the menin binding motif and DNA methyltransferase homology region within a portion of MLL are essential for their oncogenic potential, leads to leukemogenesis through a transactivation domain or an oligomerization domain within a portion of the fusion partner. MLL fusion protein, which constitutionally lacks activity of histone methyltransferase, aberrantly upregulates HOX genes by direct binding of their promoter regions. Recently, we established a multi-step leukemogenesis model where MLL fusion protein and secondary genetic alteration (s) such as FLT3 mutants cooperate to induce acute leukemia with shorter latencies, in contrast to myeloproliferative disease with long latencies by MLL fusion protein alone. Further progress in the field will provide novel insights into molecular mechanisms of MLL-mediated leukemogenesis, and help us develop direct MLL-fusion targeted therapy.
