Functional Analysis of Leukemia-associated Proto-oncoprotein MLL

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The MLL gene is a proto-oncogene that is mutated in a variety of acute leukemias. Its product is normally required for the maintenance of Hox gene expression during embryogenesis and hematopoiesis through molecular mechanisms that remain poorly defined. We have demonstrated that MLL is proteolytically processed into two fragments (MLL-N and MLL-C) that display opposite transcriptional properties and form an intra-molecular MLL complex in vivo. Leukemia-associated MLL fusion proteins lack the MLL processing sites, do not undergo cleavage, and are unable to interact with MLL-C. These observations suggest that post-translational modifications of MLL may participate in regulating its activity as a transcription factor and that this aspect of its function is perturbed by leukemogenic fusions.