MLL was first identified because it is involved in chromosomal translocations that result in leukemia. MLL is required for maintaining the proper expression of target genes, including some of the clustered HOX genes. There is growing evidence that MLL regulates gene expression by modulating chromatin structure via activity of some of its protein domains as well as through additional proteins that it recruits. Our data demonstrate that MLL protects specific CpG DNA sequences in the Hoxa9 target gene locus from methylation, thereby allowing gene expression, both of canonical Hoxa9 and of a microRNA precursor. We therefore propose a novel model of MLL function. We propose that MLL maintains the potential to express its target genes by preventing CpG island methylation during development. MLL protection from CpG methylation keeps the locus "open" and permissive for gene expression through subsequent cell divisions. This mark is not easily changed and, therefore, can function to maintain memory of previous gene expression. We will determine the role of MLL in protection from DNA methylation, the specific role of the MLL CpG DNA binding CXXC domain to MLL fusion function, and of a specific microRNA to MLL leukemogenesis.
MLL is a gene that, when involved in chromosome rearrangements, causes leukemia with a very poor prognosis. We have determined a new function of MLL with regard to how it regulates expression of other genes. We wish to further study the details of this new mechanism to advance our understanding of how MLL normally functions and how this is changed in MLL leukemia.
|Velu, Chinavenmeni S; Chaubey, Aditya; Phelan, James D et al. (2014) Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity. J Clin Invest 124:222-36|
|Risner, Laurie E; Kuntimaddi, Aravinda; Lokken, Alyson A et al. (2013) Functional specificity of CpG DNA-binding CXXC domains in mixed lineage leukemia. J Biol Chem 288:29901-10|
|Li, Zejuan; Huang, Hao; Chen, Ping et al. (2012) miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia. Nat Commun 3:688|
|Mian, Yousaf A; Zeleznik-Le, Nancy J (2010) MicroRNAs in leukemias: emerging diagnostic tools and therapeutic targets. Curr Drug Targets 11:801-11|
|Cierpicki, Tomasz; Risner, Laurie E; Grembecka, Jolanta et al. (2010) Structure of the MLL CXXC domain-DNA complex and its functional role in MLL-AF9 leukemia. Nat Struct Mol Biol 17:62-8|
|Birch, Noah W; Zeleznik-Le, Nancy J (2010) Glycogen synthase kinase-3 and leukemia: restoring the balance. Cancer Cell 17:529-31|
|Popovic, Relja; Riesbeck, Laurie E; Velu, Chinavenmeni S et al. (2009) Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood 113:3314-22|