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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087188-03
Application #
7996591
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Thomas, John
Project Start
2009-01-16
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
3
Fiscal Year
2011
Total Cost
$334,125
Indirect Cost
Name
Loyola University Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Mian, Yousaf A; Zeleznik-Le, Nancy J (2016) The miR-17?92 cluster contributes to MLL leukemia through the repression of MEIS1 competitor PKNOX1. Leuk Res 46:51-60
You, Dewen; Xin, Junping; Volk, Andrew et al. (2015) FAK mediates a compensatory survival signal parallel to PI3K-AKT in PTEN-null T-ALL cells. Cell Rep 10:2055-68
Brockway, Sonia; Zeleznik-Le, Nancy J (2015) WEE1 is a validated target of the microRNA miR-17-92 cluster in leukemia. Cancer Genet 208:279-87
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
Lokken, Alyson A; Zeleznik-Le, Nancy J (2012) Breaking the LSD1/KDM1A addiction: therapeutic targeting of the epigenetic modifier in AML. Cancer Cell 21:451-3
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
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
Mian, Yousaf A; Zeleznik-Le, Nancy J (2010) MicroRNAs in leukemias: emerging diagnostic tools and therapeutic targets. Curr Drug Targets 11:801-11

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