Grant: Operating Grant

Overall research interest. Dr. Mai studies the three-dimensional (3D) organization of the nucleus and how alterations of the nuclear organization impact on cancer development. The study subject and previous work by the applicant. This application focuses on an ideal model for human cancers: mouse chromosome 11 and blood cancers called plasmacytomas. The applicant has shown that a specific region of chromosome 11 (called 11E2) is often abnormal in aggressive plasmacytomas, while it remains normal in slow growing plasmacytomas. Goals of this study. This grant is centered around the hypothesis that the nuclear position of chromosome 11 and/or of the genes on this part of chromosome 11 can affect the aggressive behavior of this model blood cancer. To this end, the applicant proposes to 1) determine the nuclear positions and orientation of chromosome 11 in normal white blood cells as well as in slow developing vs. fast developing plasmacytomas; 2) examine for fast-developing plasmacytomas, whether chromosome 11 and/or the genes within 11E2 are found in 'activity centers' (transcription factories) that promote the level of gene activity seen only in fast developing plasmacytomas; 3) define one pathway that may lead to the nuclear repositioning of chromosome 11 and involves a protein called c-Myc. Significance of the project. The region on mouse chromosome 11 that is associated with fast-onset plasmacytoma development is conserved between mouse, rat and human. It is affected in tumors of lymphoid and non-lymphoid origin including ovarian, breast, brain and lymphoid cancers. This work will likely uncover how this conserved region allows for accelerated tumor development and may allow for the development of a test that will allow one to differentiate between slow growing vs. aggressively growing tumor cells. In the future, therapeutic strategies could be designed based on these findings.