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Mixed lineage leukemia (MLL or more specifically MLL1) is well known for its chromosomal rearrangement associated with human leukemia. During rearrangement, the MLL1 gene becomes fused with various genes present in other chromosomes, leading to either acute myeloid or lymphoid leukemia. More than 60 different MLL fusions have been identified to date, and the most frequent partners are AF4, AF6, AF9, AF10, ELL and ENL. The incidence of MLL1-associated leukemia is ∼ 3% for acute myeloid leukemia (AML) and 8–10% for acute lymphoid leukemia (ALL), and they have poor prognosis. Although it is well known that the MLL1 gene is rearranged and is closely associated with human leukemia, the exact cause of these MLL1 rearrangements is mostly unclear.

MLL proteins are evolutionarily conserved from yeast to humans and are the homolog of the Drosophila trithorax family of proteins. In humans, there are several MLL protein families such as MLL1, MLL2, MLL3, MLL4, MLL5, Set1A and Set1B. Although, the MLL1 gene is frequently rearranged in leukemia, other MLL genes are never been found to be rearranged, although they are amplified or deleted in certain tumors. At present, MLLs are recognized as histone H3 lysine 4 (H3K4)-specific methyltransferases (HMTs) that play crucial roles in gene activation. Inside cells, MLLs are present as multiprotein complexes with several common subunits. Each MLL contains diverse structural and functional domains including a SET domain that is responsible for the HMT activity. Despite the similar enzymatic activity, the complexity and multiplicity of MLLs suggest that they have crucial and distinct functions. MLLs are master regulators of HOX genes which are key players in embryonic development. Beside HOX genes, MLLs are crucial for the regulation of various other types of gene involved in cell differentiation, cell-cycle regulation, the stress response and disease.

An emerging view is that MLL-mediated H3K4 trimethylation is essential for gene activation. Gene expression may have different states: basal, activated and repressed. H3K4 trimethylation appears to be the basic requirement of both basal and activated transcription. In addition to their HMT activity, MLLs may have other co-regulatory functions during transcription activation and mRNA processing. Specifically, MLLs have one or more LXXLL (NR box) domains through which they partner with various nuclear receptors (NR) during steroid-hormone-mediated gene activation and signaling. Because MLLs are essential in NR-mediated gene regulation, it is likely that they also cross-talk with other NR co-regulators in coordinating hormone-induced gene activation and mRNA processing. Although this aspect of MLLs is rather less appreciated at present, further investigation along these lines will open up novel links between MLLs and different hormone-associated human diseases including cancer and cardiovascular diseases, and will point the way to new therapeutic avenues.

In this minireview series, we cover various structural, functional and clinical aspects of MLLs. Specifically, Ansari and Mandal emphasize the roles of MLLs in histone modification, gene expression, hormone signaling and epigenetics. Malik and Bhaumik provide a comprehensive review of evolutionary conservation in the MLL family of HMTs from yeast to humans. Marschalek focuses on MLL rearrangement, the mechanism of MLL-associated leukemias and potential therapy. Finally, Cosgrove and Patel present structural aspects of the various conserved functional domains present in MLL1. Overall, this minireview series provides ‘state-of-the-art’ information on the versatile functions of MLLs, including their roles in epigenetics, human diseases and potential therapy.

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[Subhrangsu Mandal received his bachelor’s, master’s and PhD degrees in chemistry from Midnapore College, KalyaniUniversity and the Indian Institute of Science, respectively. In 1998, he joined the University of Alberta, Canada as anAHFMR postdoctoral fellow. He later moved to the University of Medicine and Dentistry of New Jersey to researcheukaryotic transcription. In 2005, he became an Assistant Professor in the Department of Chemistry and Biochemistry atThe University of Texas at Arlington, TX, USA. His current research is aimed towards understanding the fundamentals ofgene regulation, steroid hormone signaling, epigenetics and human diseases.]