ZEB2 drives immature t-cell lymphoblastic leukemia development via enhanced tumor initiating potential and increased IL-7 receptor signaling

Early T-cell precursor leukemia (ETP-ALL) is a high-risk subtype of human leukemia that is poorly understood at the molecular level. We have recently reported translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL 1. Using a conditional gain-of-function mouse model, we have demonstrated that sustained Zeb2 expression initiates T-cell leukemia 1. Moreover, Zeb2-driven mouse leukemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling through transcriptional activation of the IL7 receptor (IL7R) 1. In addition, we have demonstrated that increased Zeb2 expression results in increased leukemia initiating cell activity 1. Here we present initial data that Zeb2 creates an aberrant self-renewal program in the DN3 thymocyte sub-population that may act as pre-leukemic stem cell that accumulates additional (epi)genetic alterations and acts as the seed of tumor formation. Using T-ALL cell lines obtained from Zeb2 Tg, p53 null and well as Zeb2 wild type, p53 null control settings we have extended our initial findings described above. Using a proteomics based approach we have found protein interactions between Zeb2 and major chromatin modulator complexes in the Zeb2 transgenic T-ALL cells. These results imply that Zeb2 may in part be transforming though alterations in both genetic and epigenetic programs. Our work reveals ZEB2 as a novel oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds (including those targeting chromatin modulators) for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model and cell lines.