Therapeutic Implications of Ventx in Acute Lymphocytic Leukemia

Abstract 2457

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, representing about a third of all pediatric cancers. Despite significant progress in ALL treatment over the past decades, relapse occurs in about 20% cases, which are often resistant to conventional chemotherapy. The canonical Wnt/b-catenin signaling has been implicated in pathogenesis of ALL, and has been a target of intensive investigation for its potential application in cancer prevention and treatment. During our recent studies, using methods of reverse genetics and developmental modeling of Xenopus embryogenesis, we identified VentX as a novel Wnt antagonist and a putative tumor suppressor in lymphocyte leukemia. On the basis of our prior findings that VentX inhibit proliferation of lymphoblastic leukemic cells, our current studies are designed to explore the potential role of VentX as a novel therapeutic target of ALL and its underlying mechanisms.

Using lymphoblastic cell model and real-time RT-PCR technique, we found that VentX expression can be induced by chemotherapeutic agents. We found that elevated expression of VentX caused a senescence phenotype in lymphoblastic leukemic cells and importantly, down-regulation of VentX expression by RNA interference technique led to strong attenuation of the cytotoxic effects of chemotherapeutic agents. Mechanistically, we found that VentX binds to the promoter and p53 and p16 and transactivates the p53/p21 and the p16/pRb senescence pathways, which have been implicated in pathogenesis of ALL. We found further that VentX control these two senescence pathways in primary B lymphocytes and that inactivation of both pathways rather than one is required to abolish the inhibitory effects of VentX on the proliferation of lymphoblastic leukemia cells.

In summary, the results of our investigation suggest that VentX is a novel therapeutic target of ALL. We found that VentX poised as a pivotal link between the oncogenic Wnt signaling pathway and the tumor suppressing senescence pathway. Given the implications of Wnt and senescence pathway in leukemia stem cells, a resource of chemo-resistance and relapse, targeting VentX may present novel opportunities for managing refractory cases of ALL and the eventual cure of the diseases.