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 #
5R01CA151319-02
Application #
8327710
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mufson, R Allan
Project Start
2011-09-02
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$375,020
Indirect Cost
$129,105
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Pekarsky, Yuri; Balatti, Veronica; Palamarchuk, Alexey et al. (2016) Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer. Proc Natl Acad Sci U S A 113:5071-6
Tili, Esmerina; Chiabai, Marcela; Palmieri, Dario et al. (2015) Quaking and miR-155 interactions in inflammation and leukemogenesis. Oncotarget 6:24599-610
Iacovelli, Stefano; Hug, Eva; Bennardo, Sara et al. (2015) Two types of BCR interactions are positively selected during leukemia development in the Eμ-TCL1 transgenic mouse model of CLL. Blood 125:1578-88
Veronese, A; Pepe, F; Chiacchia, J et al. (2015) Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia. Leukemia 29:86-95
Pekarsky, Y; Croce, C M (2015) Role of miR-15/16 in CLL. Cell Death Differ 22:6-11
Kim, Taewan; Jeon, Young-Jun; Cui, Ri et al. (2015) Role of MYC-regulated long noncoding RNAs in cell cycle regulation and tumorigenesis. J Natl Cancer Inst 107:
McClanahan, Fabienne; Riches, John C; Miller, Shaun et al. (2015) Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model. Blood 126:212-21
Balatti, Veronica; Pekarky, Yuri; Croce, Carlo M (2015) Role of microRNA in chronic lymphocytic leukemia onset and progression. J Hematol Oncol 8:12
Pekarsky, Yuri; Drusco, Alessandra; Kumchala, Prasanthi et al. (2015) The long journey of TCL1 transgenic mice: lessons learned in the last 15 years. Gene Expr 16:129-35
Bresin, Antonella; Callegari, Elisa; D'Abundo, Lucilla et al. (2015) miR-181b as a therapeutic agent for chronic lymphocytic leukemia in the Eµ-TCL1 mouse model. Oncotarget 6:19807-18

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