ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling

Abstract

Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model.

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

“…Strikingly, this analysis revealed specific, hormone-dependent deregulation of 2332 (1205 down; 1127 up) and 3205 genes (1456 down; 1749 up) in CAL-1 shGCR and CAL-1 GCR-FP dexamethasone-treated cells, respectively, compared with CAL-1 control cells. Further analysis revealed a common subset of 264 deregulated genes (139 down; 125 up) ( Figure 3B; supplemental Table 13), which included known GCR target genes such as PFKB2 (encoding 6-phosphofructo-2-kinase) and genes encoding nuclear factors that have been implicated in normal (IKZF2/Helios) or leukemic (ZEB2) T lymphoid 39,40 or dendritic cell lineage development (SPIB). 41 Supporting the clinical relevance of the latter findings, deregulated expression of IKZF2, ZEB2, and SPIB was also observed by GEP in primary patient cells with NR3C1 deletion compared with nondeleted control cases (supplemental Figure 3A).…”

Direct interaction between miR-203 and ZEB2 suppresses epithelial–mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance

“…It is an oncogenic transcription factor which induces epithelial-mesenchymal transition (EMT) in tumors by binding to and regulating E-cadherin [9]. In a previous study, ZEB2 was found to inhibit squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma by repressing DNp63 through YAP [10] and stimulate immature T-cell lymphoblastic leukemia development via enhanced tumor-initiating potential and IL-7 receptor signaling [11]. In addition, ZEB2 modulated by miR-200b or TMPRSS was associated with EMT and multidrug resistance in lung cancer [12,13].…”

From EMT to HSC to AML: ZEB2 is a cell fate switch

“…The EMN study did not delineate outcome on the basis of the patients' MYD88 mutation status, nor could the patients be longitudinally evaluated for clonal evolution, a phenomenon that has recently been documented in WM with both PI-based and Bruton tyrosine kinase inhibitor-based therapies. 9 Finally, and most importantly, collaborative efforts remain indispensable in the face of sparse high-level evidence to inform hematologists of the optimal approach to managing WM, a rare and, to date, incurable malignancy. The WM1 study, a phase 3 international trial, demonstrated how consequential the choice of initial therapy can be, even for a typically indolent disorder such as WM; the use of frontline fludarabine favorably affected survival (see table) compared with chlorambucil.…”

“…Moving forward, additional work needs to be done to more precisely elucidate the molecular mechanisms at play and to investigate the potential development and use of ZEB2 pathway inhibitors as an antileukemic therapy. Such a therapy will likely have a wide range of applicability not only for AML but also in early T-cell precursor acute lymphoblastic leukemia 9 and solid cancers such as breast, 10 colorectal, 11 and liver cancers. 12 However, careful consideration will need to be given to limit the toxicity of this type of differentiation therapy on the remaining normal immune cell populations, which also rely on ZEB2.…”