Multiple myeloma (MM) is one of the most common hematological neoplasms, constituting about 1% of all human cancers and 2% of all cancer deaths. MM is preceded by monoclonal gammopathy of undetermined significance (MGUS), one of the most common pre-cancerous conditions afflicting 3% of the United States population over 50 years old. Although MM is regarded as an environmental disease, it is not yet clear what promotes the progression from MGUS to the deadly MM. One of the unique features of MM is the extremely low mutation rate of the tumor suppressor p53 gene. Genomic instability (chromosome translocation, aneuploidy, and gene mutation) is widely observed in MM cases, suggesting that the function of p53 as the guardian of the human genome is compromised. We previously analyzed the molecular mechanisms of p53 inactivation in MM cells by a new class of noncoding small RNAs, microRNAs (miRNAs). Data from our laboratory and others have shown that multiple miRNAs suppress expression of the human p53 gene and that a majority of these miRNAs are overexpressed in MM. We hypothesize that the ubiquitous environmental pollutants benzo[a]pyrene (BaP) and tetrachlorodibenzodioxin (TCDD) disrupt functional interactions of miRNA:p53 to mediate p53 inactivation over the course of MM. In this renewal application, we propose 3 specific aims to advance our investigations into the molecular etiology of MM and identify potential treatment and preventive strategies.
In Aim 1, we will dissect the underlying mechanisms of upregulation of miRNAs in MM cells exposed to BaP and TCDD.
In Aim 2, we will determine, using murine syngeneic xenograft and genetic models, whether BaP directly promotes MM progression via one miRNA gene cluster that targets p53.
In Aim 3, we will determine whether epigallocatechin gallate (EGCG, the main component in the botanical drug Polyphenon(R) E) prevents or inhibits MM progression induced by BaP or TCDD. Completion of the goals in this proposal will reveal the role of environmental hydrocarbons in p53:miRNA interaction and in MM etiology and provide a repurposed drug for MM prevention and therapeutic intervention.

Public Health Relevance

The proposed research will provide a better understanding of the role of environmental toxicants in the interaction of miRNAs and the p53 pathway over the course of MM development. By using EGCG (a natural compound in green tea) to modulate the expression of miRNAs for p53 reactivation, our work will identify an accessible option to treat MM with no p53 mutations. In addition, these studies may result in new strategies of cancer prevention for over a million individuals with MGUS, a pre-malignant condition that precedes virtually all cases of MM.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA138688-06A1
Application #
8761249
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Johnson, Ronald L
Project Start
2009-04-01
Project End
2018-08-31
Budget Start
2014-09-04
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
$353,787
Indirect Cost
$106,074
Name
University of Louisville
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40202
de Winde, Charlotte M; Veenbergen, Sharon; Young, Ken H et al. (2016) Tetraspanin CD37 protects against the development of B cell lymphoma. J Clin Invest 126:653-66
Deng, L; Xu-Monette, Z Y; Loghavi, S et al. (2016) Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era: a report from the International PTL Consortium. Leukemia 30:361-72
Loghavi, Sanam; Wang, Sa A; Jeffrey Medeiros, L et al. (2016) Immunophenotypic and diagnostic characterization of angioimmunoblastic T-cell lymphoma by advanced flow cytometric technology. Leuk Lymphoma 57:2804-2812
Xia, Yi; Jeffrey Medeiros, L; Young, Ken H (2016) Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies. Biochim Biophys Acta 1865:58-71
Xu-Monette, Zijun Y; Zhang, Shanxiang; Li, Xin et al. (2016) p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function. Aging (Albany NY) 8:345-65
Kanagal-Shamanna, Rashmi; Xu-Monette, Zijun Y; Miranda, Roberto N et al. (2016) Crystal-storing histiocytosis: a clinicopathological study of 13 cases. Histopathology 68:482-91
Cao, Xin; Medeiros, L Jeffrey; Xia, Yi et al. (2016) Clinicopathologic features and outcomes of lymphoplasmacytic lymphoma patients with monoclonal IgG or IgA paraprotein expression. Leuk Lymphoma 57:1104-13
Yu, Li; Li, Ling; Medeiros, L Jeffrey et al. (2016) NF-κB signaling pathway and its potential as a target for therapy in lymphoid neoplasms. Blood Rev :
Ye, Qing; Xu-Monette, Zijun Y; Tzankov, Alexandar et al. (2016) Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma. Oncotarget 7:2401-16
Xu-Monette, Zijun Y; Deng, Qipan; Manyam, Ganiraju C et al. (2016) Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma. Clin Cancer Res 22:3593-605

Showing the most recent 10 out of 58 publications