Research

Katsantoni Group focuses on the study of transcriptional regulation in normal and pathologic hematopoiesis. The Group is trying to understand the role of signal transducers and activators of transcription (STATs), which are latent cytoplasmic transcription factors that transduce signals from activated cell surface receptors to the nucleus to modulate transcription. STATs are of particular interest as they are activated by a variety of cytokines, constituting important components of various signal transduction pathways. JAK-STAT constitute a characteristic example of a deregulated signaling pathway involved in carcinogenesis and constitutive activation of STATs is a hallmark for both hematopoietic and solid malignancies. STATs are also implicated in stress and immunity mechanisms. In erythropoiesis, STAT5 is one of the principal secondary messengers activated by the erythropoietin receptor. The Group is mainly focusing on understanding the role of STAT3 and STAT5, and addresses investigations on:

1. The mechanisms of gene transcription controlled by the STATs and by the interactions of STATs with other factors in normal and pathologic hematopoietic cells. The functions of the STAT target gene networks and interacting partners are investigated in a temporal and spatial manner.
2. The mechanisms of STATs in leukemic transformation.
3. The mechanisms of STATs and other transcription factors in ineffective erythropoiesis.

The Group applies (a). genomics and transcriptomics approaches for identification of transcription factor target genes (Figures 1, 2, 3) and (b). tagging methodologies and labeling proteomic approaches coupled to mass spectrometry to identify protein complexes of STATs. Bioinformatics tools are used to facilitate target genes and protein networks analysis. Primary human cell cultures and cell lines models are used, including pro-B, thalassemic (model of ineffective erythropoiesis), myelodysplastic syndrome (model of ineffective erythropoiesis and pre-leukemia) and acute myeloid leukemia (model of leukemia) cells. Identification of interacting partners and/or target genes of STATs provides novel therapeutic targets for treating malignancies and other pathologies linked with STATs activation. Furthermore, STAT target genes constitute potential biomarkers for stratification and therapeutic management of the patients.

The main current scientific directions of the Group include the following:

1. Identification of two novel STAT5 interacting partners (LSD1 and HDAC3) and their dual role in STAT5-dependent transcription (Nucleic Acids Res. 2017) in pro-B cells took place. Based on these findings, investigations of the 3D nuclear structure of STAT5, LSD1 and HDAC3 target genes are ongoing, to define whether repressive and activating nuclear territories exist. The Group also investigates the role of STATs in B-cell chronic lymphocytic leukemia (B-CLL) cells.
2. The Group is focusing on the understanding of the role of STAT3 and STAT5 in pre-leukemia to leukemia transformation. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are used as models for pre-leukemia and leukemia respectively, and STAT3 and STAT5 target gene networks role in leukemic transformation is currently studied. Potential STAT inhibitors to prevent leukemic transformation are also studied.
3. The Group is unraveling the role of STATs and other transcription factors in normal and ineffective erythropoiesis. Transcriptomic signatures of erythroid progenitor cells have determined sex specific differences in thalassemia (Haematologica. 2021). Currently integrations of RNA-seq with proteomics data take place to further investigate the findings, with the goal to apply them in various diseases with underlying ineffective erythropoiesis, including thalassemia and MDS.