The goal of this project is to further elucidate the role of LKB1 in lymphocyte biology, metabolism and transformation. The LKB1 (Liver Kinase B1) gene, also known as serine threonine kinase 11 (STK11), was originally identified as the causative mutation in patients with Peutz-Jeghers syndrome (PJS), which is characterized by gastrointestinal polyps and increased cancer risk later in life. Furthermore, somatic mutations in LKB1 have been observed in patients with lung cancer, pancreatic, cervical and biliary carcinomas, and melanoma. Lkb1's function as a tumor suppressor was not surprising since it regulates biological functions that are relevant to cancer, such as cell metabolism through the AMPK pathway, polarity, invasion and migration. In lung cancer, LKB1 mutations have been observed concurrently with activating mutations in the KRAS oncogene. Mouse models of these synergistic mutations have demonstrated that Lkb1 haploinsufficiency cooperates with oncogenic KrasG12D to decrease lung tumor latency and increase metastatic potential. In the hematopoietic system, where activating Kras mutations have been identified in B and T cell lymphoblastic leukamias, Lkb1 deletion results in depletion of the HSC compartment due to apoptosis, with no apparent oncogenic activity. Lkb1 must therefore have a very diverse repertoire of functions depending on the molecular context and appears to function as a tumor suppressor only within the context of another oncogene, like activated Kras. This project will attempt to understand the specific functions of Lkb1 during lymphocyte development and metabolism, both in the presence and absence of an activated Kras allele. Understanding the mechanisms that govern lymphocyte survival will not only help improve our understanding of basic immunology and hematopoiesis, but also help us better understand the oncogenic pathways these genes are part of. Furthermore, the genetic interaction between a tumor suppressor providing a strong death signal like Lkb1 in the hematopoietic signal, and an oncogene with a strong survival signal, like activated Kras, will help us elucidate the mechanisms during malignant transformation and contribute to creating better therapeutic strategies.
Numerous genes have been associated with cancers of the hematopoietic system, such as acute leukemias and lymphomas. The study of the molecular mechanisms these genes are involved in will not only enrich our knowledge of molecular biology, but it is of tremendous clinical importance. Unraveling the mechanistic details of the genetic interactions in malignancies will help generate more effective therapeutic strategies to treat these diseases that are a huge burden on our socioeconomic and healthcare system.
|Souroullas, George P; Jeck, William R; Parker, Joel S et al. (2016) An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med 22:632-40|