Thomas-Tikhonenko Laboratory

Research

Our laboratory is broadly interested in the mechanisms of neoplastic transformation by the Myc family oncoproteins (including c- and N-Myc) and Myc-regulated non-coding microRNAs. To determine the contribution of Myc to malignant growth in hematopoietic tissues, we have developed a new mouse model for B-cell lymphoma based on infection of p53-null bone marrow progenitors by a Myc-encoding retrovirus (Yu et al, Blood 2007; Cozma et al, J Clin Invest 2007; Amaravadi et al, J Clin Inv, 2007). In this system, the salient features of Myc-induced lymphomagenesis are overexpression of the oncogenic miR-17-92 microRNA cluster and simultaneous repression of several tumor suppressive microRNAs, such as miR-15/16 and miR-34 (Chang et al, Nature Genet 2008 & Proc Natl Acad Sci 2009, Sotillo et al, Oncogene 2011). These microRNAs help sustain c-Myc levels and contribute to deregulation of multiple Myc target genes, B-cell receptor signaling, and therapeutic apoptosis.

Additionally, in solid tumors such as pediatric neuroblastoma, glioblastoma, and colon adenocarcinoma, deregulation of miR-17-92 leads to profound suppression of TGFβ signaling and sharply diminished production of many anti-angiogenic factors such as thrombospondin-1 and clusterin (Dews et al, Nature Genet 2006 & Cancer Res 2010; Chayka et al, J Natl Cancer Inst 2009, Mestdagh et al, Mol Cell 2010, Sundaram et al, Cancer Res 2011). This brings about robust tumor neovascularization and enhanced neoplastic growth. Overall, our work (and that of our collaborators) promulgated the idea that transcription factors such as c-Myc perform many of their functions not just via binding to target gene promoters but also by regulating select sets of microRNAs. This flexibility allows Myc to influence (albeit subtly) many more genes than a canonical transcription factor could. We take pride in the fact that our two first two papers on this subject (Nature Genetics 2006 and 2008) continue to be frequently cited (>300 times each), attesting to their sustained influence in the field.