E2A translocations in pediatric leukemia: developing new therapeutic targets

Precursor B-cell acute lymphoblastic leukemia is the most common cancer in children. In approximately 10% of patients with precursor B-cell ALL, the transcription factor E2A is involved in a chromosomal translocation. Three translocations have been identified: t(1;19), t(17;19), and inv(19), which fuse E2A to the genes PBX1, HLF, and FB1, respectively. Available models, including murine bone marrow culture, transgenic mice, and cell lines, have not elucidated the mechanism of E2A-translocation associated leukemogenesis, as precursor B-cell leukemia does not occur in these experimental systems. In three different assays, we have found that the N-terminal portion of E2A, common to the three translocations, has unexpected biological activity that is consistent with promotion of B-cell expansion. Previous models have not shown activity of this protein fragment. In the current work, we will determine the minimal functional domains needed for the activity of this protein fragment. WE will also use co-immunoprecipitation to identify proteins that interact with this region of E2A. These two approaches will enable the development of blocking peptides as a novel targeted biologic therapy for precursor B-cell ALL.