Multiple myeloma (MM) is one of the most common hematological neoplasms. It constitutes about 1% of human cancers and 2% of all cancer deaths. Polycylic aromatic hydrocarbons such as 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) have been closely correlated to MM by epidemiologic studies, yet the biologic mechanisms of a causal relationship between TCDD exposure and MM have not been well understood. One of the unique features of MM compared to other cancers is the extremely low genetic mutation rate of the tumor protein p53 (TP53) gene. TP53 encodes the p53 tumor suppressor, guardian of the human genome. Genomic instability (chromosome translocation, aneuploidy, and gene mutation) is widely observed in MM and reveals that the function of p53 as the guardian of the human genome is compromised in MM. We explored the molecular mechanisms of p53 inactivation in MM by a new class of noncoding small RNAs, microRNAs (miRNAs) as recent reports have demonstrated that some miRNAs such as miR-34 are important players in the p53 tumor suppressor network. We hypothesize that miRNAs negatively regulate the human TP53 gene in MM. We propose three aims for this project: first, we will identify miRNAs that target the human TP53 gene by a combination of mutagenesis, reporter expression, and immunoblotting analyses;second, we will assess the pathological significance of miRNA:TP53 interactions in MM cell lines and primary MM cells by expression profiling and miRNA inhibition assays;third, we will determine whether dioxin modulates p53 signaling by upregulating miRNA expression. A novel p53 inactivation mechanism by an miRNA, that is upregulated by dioxin, will lead to unique targets for diagnostic markers and therapeutic interventions in MM patients as well as provide a better understanding of the biological interactions between dioxin exposure and MM tumorigenesis.

Public Health Relevance

TP53 gene alterations are rare and late events in multiple myeloma (MM), the second most common hematological malignancy constituting about 1% of all human cancers. It is critical to explore whether there are unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MM development. The proposed research plan is to test the hypothesis that TP53 is negatively regulated by microRNAs (miRNAs), a class of newly discovered small noncoding RNAs, to define whether miRNA dysregulation contributes to tumorigenesis prior to TP53 gene alterations, and to determine whether dioxin modulates p53 signaling through upregulating miRNA expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138688-03
Application #
8066379
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Johnson, Ronald L
Project Start
2009-07-01
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2011
Total Cost
$150,411
Indirect Cost
Name
University of Louisville
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Zhang, Jun; Medeiros, L Jeffrey; Young, Ken H (2018) Cancer Immunotherapy in Diffuse Large B-Cell Lymphoma. Front Oncol 8:351
Xi, Jiajia; Huang, Qian; Wang, Lei et al. (2018) miR-21 depletion in macrophages promotes tumoricidal polarization and enhances PD-1 immunotherapy. Oncogene 37:3151-3165
Yao, Z; Deng, L; Xu-Monette, Z Y et al. (2018) Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy. Leukemia 32:353-363
Xu-Monette, Zijun Y; Zhou, Jianfeng; Young, Ken H (2018) PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood 131:68-83
Visco, Carlo; Wang, Jinfen; Tisi, Maria Chiara et al. (2017) Hepatitis C virus positive diffuse large B-cell lymphomas have distinct molecular features and lack BCL2 translocations. Br J Cancer 117:1685-1688
Cai, Qingqing; Tu, Meifeng; Xu-Monette, Zijun Y et al. (2017) NF-?B p50 activation associated with immune dysregulation confers poorer survival for diffuse large B-cell lymphoma patients with wild-type p53. Mod Pathol 30:854-876
Xu-Monette, Zijun Y; Zhang, Mingzhi; Li, Jianyong et al. (2017) PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response? Front Immunol 8:1597
Sun, Ruifang; Wang, Jinfen; Young, Ken H (2017) Oncogenic Signaling Pathways and Pathway-Based Therapeutic Biomarkers in Lymphoid Malignancies. Crit Rev Oncog 22:527-557
Ok, Chi Young; Young, Ken H (2017) Targeting the programmed death-1 pathway in lymphoid neoplasms. Cancer Treat Rev 54:99-109
Yu, Li; Tu, Meifeng; Cortes, Jorge et al. (2017) Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease. Blood 129:1658-1668

Showing the most recent 10 out of 75 publications