Despite recent progress in cancer research, the ability to treat and prevent plasma-cell (PC) myeloma, the second most common hematologic cancer in the United States, remains severely limited. Addressing the current limitations will require additional research efforts, including projects that will lead to an enhanced understanding of the genetic pathways underlying malignant PC transformation. The long-term goal of this research program is to improve the outcome of myeloma and related PC neoplasms. The main objective of the proposed research, which represents an important step towards attaining the long-term goal, is to gain insight into the genetic pathways that drive PC transformation. Our central hypothesis is that unbiased genetic forward screening in mice that are genetically prone to PC malignancy will uncover candidate cancer driver genes that can be evaluated across the mouse-human species barrier in order to detect and validate orthologous driver genes in human PC tumors. Three specific research aims are proposed to test the central hypothesis and achieve the main objective of this application.
Aims 1 and 2 are concerned with identifying candidate cancer driver genes in retrovirus- and transposon-based cancer screens in the iMyc?E? transgenic mouse, a gene-insertion model of the Myc-activating T(12;15) translocation in mouse plasmacytoma.
Aim 3 is devoted to validating the newly discovered driver genes, including the involvement of their human orthologs in human PC tumors. The studies in Aim 1 will rely on a modified Moloney murine leukemia virus, MOL4070LTR. The studies in Aim 2 will take advantage of a double-transgenic Sleeping Beauty (SB) somatic mutagenesis system that uses the inducible transposase, SB11, to unleash the mutagenic transposon, T2/Onc2, in PCs. The studies in Aim 3 will first employ bioinformatics tools for gene validation, and then follow up with biochemical, molecular genetic and biological methods to assess the potential of selected driver genes as new targets for cancer therapy and prevention. Supported by strong preliminary results that provide a sound rationale for this application, the proposed research is poised to facilitate novel targeted approaches to the therapy and prevention of PC neoplasia.

Public Health Relevance

Plasma-cell myeloma, commonly known as multiple myeloma, is the most prevalent and fatal plasma-cell neoplasia and the second-most common hematologic malignancy worldwide. The research proposed here will take advantage of two complementary, unbiased, genetic-forward screenings in a Myc-transgenic mouse model of human plasma-cell neoplasia to enhance our understanding of the genetic pathways underlying malignant plasma-cell transformation and inspire new targeted approaches to the treatment and prevention of human plasma-cell neoplasms.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA151354-05
Application #
8677776
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Howcroft, Thomas K
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Rabellino, Andrea; Melegari, Margherita; Tompkins, Van S et al. (2016) PIAS1 Promotes Lymphomagenesis through MYC Upregulation. Cell Rep 15:2266-78
Gu, C; Yang, Y; Sompallae, R et al. (2016) FOXM1 is a therapeutic target for high-risk multiple myeloma. Leukemia 30:873-82
Rosean, T R; Holman, C J; Tompkins, V S et al. (2016) KSHV-encoded vIL-6 collaborates with deregulated c-Myc to drive plasmablastic neoplasms in mice. Blood Cancer J 6:e398
Tompkins, V S; Rosean, T R; Holman, C J et al. (2016) Adoptive B-cell transfer mouse model of human myeloma. Leukemia 30:962-6
Zhang, Laiqun; Blackwell, Ken; Workman, Lauren M et al. (2015) RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival. Mol Cell Biol 35:3324-38
Han, Seong-Su; Tompkins, Van S; Son, Dong-Ju et al. (2015) CDKN1A and FANCD2 are potential oncotargets in Burkitt lymphoma and multiple myeloma. Exp Hematol Oncol 4:9
Franqui-Machin, Reinaldo; Wendlandt, Erik B; Janz, Siegfried et al. (2015) Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction? Oncotarget 6:40496-506
Rosean, T R; Tompkins, V S; Olivier, A K et al. (2015) The tumor microenvironment is the main source of IL-6 for plasma cell tumor development in mice. Leukemia 29:233-7
Yang, Ye; Shi, Jumei; Gu, Zhimin et al. (2015) Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma. Cancer Res 75:594-604
Zhou, W; Yang, Y; Gu, Z et al. (2014) ALDH1 activity identifies tumor-initiating cells and links to chromosomal instability signatures in multiple myeloma. Leukemia 28:1155-8

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