TAL1 as a master oncogenic transcription factor in T-cell acute lymphoblastic leukemia

In hematopoietic cell development, the transcriptional program is strictly regulated in a lineage- and stage-specific manner that requires a number of transcription factors to work in a cascade or in a loop, in addition to interactions with nonhematopoietic cells in the microenvironment. Disruption of the transcriptional program alters the cellular state and may predispose cells to the acquisition of genetic abnormalities. Early studies have shown that proteins that promote cell differentiation often serve as tumor suppressors, whereas inhibitors of those proteins act as oncogenes in the context of acute leukemia. A prime example is T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder characterized by clonal proliferation of immature stage thymocytes. Although a relatively small number of genetic abnormalities are observed in T-ALL, these abnormalities are crucial for leukemogenesis. Many oncogenes and tumor suppressors in T-ALL are transcription factors that are required for normal hematopoiesis. The transformation process in T-ALL is efficient and orchestrated; the oncogene disrupts the transcriptional program directing T-cell differentiation and also uses its native ability as a master transcription factor in hematopoiesis. This imbalance in the transcriptional program is a primary determinant underlying the molecular pathogenesis of T-ALL. In this review, we focus on the oncogenic transcription factor TAL1 and the tumor-suppressor E-proteins and discuss the malignant cell state, the transcriptional circuit, and the consequence of molecular abnormalities in T-ALL.