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Notch1 receptor signaling is essential for T cell fate specification and physiological thymic T lymphocyte development. Its dysregulation and oncogenic activation are detected in almost 80% of pediatric patients suffering from T cell acute lymphoblastic leukemia (T-ALL). T-ALL is a hematological neoplasm arising from immature thymocytes. T cell factor 1 (Tcf1) is a crucial well-known transcription factor regulating the early stages of thymocyte maturation and Notch1 directly drives the expression of Tcf1 during normal T cell development. Here we assessed the role of Tcf1 in modulating chromatin topology which enables the initiation of T-ALL at the level of early hematopoietic progenitors. This allows for the discovery of stage-setting epigenetic regulators establishing a leukemia-prone chromatin landscape during Notch1-driven disease initiation. We found Tcf1 to be an essential mediator of Notch1 signaling during T-ALL induction. Inactivation of Tcf1 prevented leukemogenesis despite oncogenic Notch1 activation. Genomic analysis of hematopoietic progenitors revealed T cell lineage specification to be essential in T-ALL initiation prior to the appearance of phenotypic features of T cells. The expression of genes associated with the T cell lineage was dependent on Notch1 and Tcf1. Chromatin accessibility, chromosome conformation capture and ChIP-seq analysis revealed the co-regulatory epigenetic function of Notch1 and Tcf1 in imprinting a leukemic chromatin landscape. Epigenetic modulation of distal enhancers which regulate leukemic oncogenes has been well described in patient-derived T-ALL cells. The Notch1-Myc enhancer region was shown to be indispensable in the process of leukemogenesis. We have identified a novel regulatory locus, dependent on Tcf1 and Notch1, essential for the expression of Myc in pre-T-ALL cells. This genomic region termed Tcf1-regulated Myc enhancer (TMe) was highly conserved across species. TMe was essential for the transition of pre-leukemic cells to a transplantable full-blown T-ALL but was dispensable for the physiological development of T cells. After activation of the enhancer in hematopoietic progenitors, this regulatory site remained accessible and bound by Tcf1 in murine and human T-ALL cells. Tcf1 is therefore required for shaping the epigenetic landscape of hematopoietic progenitors overexpressing oncogenic Notch1, and thus regulates the expression of genes involved in leukemogenesis.
Jonas Caspar De Tribolet-Hardy
Freddy Radtke, Ute Koch, Christelle Dubey, Nadine Zangger, Mateusz Waldemar Antoszewski, Marianne Nkosi, Tara Kimberly Sugrue, Giovanni Ciriello