Abstract LB-034: Tcf7: an Essential Mediator in Notch-induced T-ALL

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer caused by the malignant transformation of immature thymocytes. Notch1 gain-of-function mutations are present in >50% of T-ALL cases and result in the constitutive activation of Notch1 intracellular domain (N1ICD) in mutated cells. The mechanisms by which deregulated Notch1 signalling leads to T-ALL development are currently unresolved and stringently investigated. T cell factor-1 (TCF-1) is a transcription factor encoded by Tcf7. Not only playing crucial roles in Wnt signalling, Tcf7 is (i) a direct Notch1 target gene and (ii) required for driving early T lineage commitment of hematopoietic progenitors. Together, these findings suggest that Tcf7 may play a role in Notch1-driven T-ALL. Herein, we show that the conditional loss of Tcf7 in hematopoietic progenitors prevents T-ALL development in both genetic- and retroviral-based mouse models of N1ICD over-expression. However, T-ALL development was unaffected by conditional loss of the Wnt signalling mediator, β-catenin. Interestingly, conditional Tcf7 deficiency partially restored the B lineage potential of N1ICD over-expressing bone marrow progenitors. Similar to Tcf7-/- mice, conditional Tcf7 deficiency in bone marrow progenitors abrogated T cell development in adult thymi. However, unexpectedly, Tcf7-deficient hematopoietic progenitors adopted a B cell fate in these thymi, a phenotype that was found to be comparable to conditional loss of Notch1. Overall, our results indicate that Tcf7 is an important mediator of Notch1-driven T-ALL. Furthermore, our data suggests that, in addition to promoting T lineage commitment, Tcf7 may also function as a Notch1-dependent transcriptional repressor of B lineage commitment in adult hematopoiesis. We performed RNAseq to identify the molecular players involved in Tcf7-mediated lineage repression and complement this approach with CHIP_Seq. Citation Format: Ute Koch, Tara Sugrue, Christelle Dubey, Freddy Radtke. Tcf7: an essential mediator in Notch-induced T-ALL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-034.