T lymphocyte lineage acute lymphoblastic leukemia is a malignancy that occurs in children and adults and is predicted to increase in incidence as the average age of the American population increases. While multiple oncogenes and tumor suppressors have been implicated in this disease greater than 60% of T-ALL cases have mutations that decreased the function of the E2A transcription factors. Moreover, mice lacking E2A proteins develop a T-ALL-like malignancy, a finding that led to the hypothesis that E2A proteins are tumor suppressors. In this grant application we will test an opposing hypothesis, that the immune deficiency created by loss of E2A proteins results in a loss of early thymocyte progenitor competition and that this loss of competition drives the development of T-ALL like disease. We will test our hypothesis by examining the ability of wild-type thymocyte progenitors to suppress transformation of E2A-deficient thymocytes and by testing whether the degree of immune deficiency in E2A-deficient mice is sufficient to promote transformation of WT cells using a novel model of thymic engraftment. We will also test the impact of increasing thymocyte progenitor competition on the gene expression program of E2A-deficient T cell progenitors to identify gene signatures that are regulated by immune deficiency as opposed to E2A-deficiency. Our experiments will provide significant insight into the mechanism of T cell transformation and may reveal that immune system decline is a precursor to T-ALL susceptibility.
Our study will provide insight into the mechanisms leading to T cell transformation in E2A-deficient mice. Since inhibition of E2A function is a major mechanism in human T-ALL our results may point to a role for immune deficiency in the initiation of this disease. Consequently, a role for T cell progenitor decline in human T- ALL could be investigated.
|Verykokakis, Mihalis; Kee, Barbara L (2017) Applying the TOR(C)QUE in iNKT cells: A new twist in an old tale. Eur J Immunol 47:454-457|