Chronic lymphocytic leukemia (CLL) is the most common form of human leukemia. It affects individuals over 50 years of age and it manifests either as an indolent or an aggressive disease. Often, with time, the indolent disease progresses to the aggressive form. Thus, the clinical approach to the disease is "wait and watch", since it may be counterproductive to treat patients with indolent CLL with aggressive chemo/immunotherapy. CLL is characterized by consistent chromosomal alterations, the most common of which is a deletion at 13q14 that is observed by cytogenetics in over 50% of cases. We have shown that this deletion consistently involves two microRNA genes, miR-15a and miR-16-1, which are knocked out or down in approximately 70% of CLL patients. These microRNAs target directly BCL2 and indirectly MCL1, two genes dysregulated in CLL. We also found that loss of miR-15a and 16-1 is associated with the development of the indolent form of the disease. We have also cloned the TCL1 gene responsible for the development of prolymphocytic T cell leukemia through t(14;14)(q11;q32) translocations or inv(14)(q11;32) inversions and then shown that this gene is overexpressed in the aggressive form of human CLL. Recently, we have constructed a TCL1 transgenic mouse model that overexpresses the human TCL1 gene in B cells. TCL1 transgenic mice develop the aggressive form of CLL that resembles quite closely, if not exactly, the human form of the disease. We also developed two mouse models for the indolent form of the disease by taking advantage of our understanding of microRNA dysregulation in CLL. We propose to use our mouse models to identify most of the genes involved in the multistep process responsible for the pathogenesis of human CLL, including familial CLL. The results of these studies will be compared to those in human CLLs. By taking advantage of our new mouse models, we also propose to develop novel microRNA-based therapies for CLL by targeting the expression of critical oncogenes.

Public Health Relevance

We propose to identify genetic and epigenetic changes responsible for the progression of chronic lymphocytic leukemia (CLL), the most common human leukemia. To achieve our goal, we have developed mouse CLL models that recapitulate the changes observed in human CLL. We propose to use these mouse models to identify the critical changes responsible for CLL progression and to develop novel targeted therapies for this incurable disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151319-04
Application #
8700333
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mufson, R Allan
Project Start
2011-09-02
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$363,375
Indirect Cost
$125,096
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Liu, J; Chen, G; Feng, L et al. (2014) Loss of p53 and altered miR15-a/16-1?MCL-1 pathway in CLL: insights from TCL1-Tg:p53(-/-) mouse model and primary human leukemia cells. Leukemia 28:118-28
Acunzo, Mario; Romano, Giulia; Wernicke, Dorothee et al. (2014) Translocation t(2;11) in CLL cells results in CXCR4/MAML2 fusion oncogene. Blood 124:259-62
Widhopf 2nd, George F; Cui, Bing; Ghia, Emanuela M et al. (2014) ROR1 can interact with TCL1 and enhance leukemogenesis in E?-TCL1 transgenic mice. Proc Natl Acad Sci U S A 111:793-8
Tili, Esmerina; Michaille, Jean-Jacques; Croce, Carlo M (2013) MicroRNAs play a central role in molecular dysfunctions linking inflammation with cancer. Immunol Rev 253:167-84
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Zanesi, Nicola; Balatti, Veronica; Riordan, Jesse et al. (2013) A Sleeping Beauty screen reveals NF-kB activation in CLL mouse model. Blood 121:4355-8
Chen, Shih-Shih; Batliwalla, Franak; Holodick, Nichol E et al. (2013) Autoantigen can promote progression to a more aggressive TCL1 leukemia by selecting variants with enhanced B-cell receptor signaling. Proc Natl Acad Sci U S A 110:E1500-7