Andrei Thomas-Tikhonenko Laboratory

Led by Andrei Thomas-Tikhonenko, PhD, researchers in the Thomas-Tikhonenko Laboratory are studying the effects of Myc oncogene-induced deregulation of microRNAs in hematopoietic malignancies and solid tumors such as pediatric neuroblastoma. The long-term goal of the work in the Thomas-Tikhonenko Laboratory is to define the contribution of Myc-induced deregulation of microRNAs to dysregulated neoplastic growth and to identify new targeted therapies to treat pediatric cancers and solid tumors.

Ongoing research in this laboratory using newly developed human B-lymphoid cell lines and mouse models of B cell lymphoma revealed that overexpression of the oncogenic miR-17-92 microRNA gene cluster and repression of several tumor suppressor microRNAs was responsible for development Myc-induced lymphomas. Subsequent studies showed that deregulation of miR-17-92 also interfered with B-cell receptor (BCR) signaling and may contribute to development of Myc-induced B cell lymphomas.



Other studies in the Thomas-Tikhonenko Laboratory demonstrated that overexpression of miR-17-92 in pediatric neuroblastomas exerted tumorigenic effects by suppressing expression of TGFβ-inducible anti-angiogenic genes such as thrombospondin-1, connective tissue growth factor (CTGF) and clusterin. This indicated that deregulation of the miR-17-92 cluster can alter tumor microenvironments via enhanced tumor angiogenesis/vascularization and dysregulated tumor cell growth.

Additional studies, using a series of genetically-complex human and mouse colorectal cancer (CRC) cell lines, indicated that either Myc gene activation or TGFβ gene inactivation, but not both, promoted tumor angiogenesis and cell growth.  These findings suggested that Myc oncogene activation and loss of function mutations in TGFβ genes in human CRC are functionally redundant and may exhibit masking epistatic genetic interactions.

Loss of effectiveness of chimeric antigen receptor armed T cells against CD19 (CART-19) immunotherapy has been reported in children with B cell acute lymphoblastic leukemia (B-ALL). Genomic and biochemical studies conducted in the Thomas-Tikhonenko Laboratory found that selection of alternately spliced CD19 protein isoforms, rather than mutations in the coding sequence of the CD19 gene, was responsible for CD19 epitope loss after CART19 therapy in children with B-ALL. New studies are underway to more clearly define the molecular underpinnings of this unique mechanism of resistance to CART19 immunotherapy.

Future studies in the Thomas-Tikhonenko Laboratory will focus on more clearly defining the relationship between Myc-induced deregulation of miR-17-92 and BCR signaling, the impact of miR-17-92 deregulation on alteration of neuroblastoma tumor microenvironments, development of molecular tests to preselect patients who may respond to cancer therapies based on epistatic profiling of tumor types and creation of modified CART19 cells that can be used to treat relapsed or refractory pediatric patients with B-ALL.