A recent study from Steven Goossens and Enrico Radaelli shows that ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and ​IL-7 receptor signaling.

First, they observed increased ​ ZEB2 levels in the paediatric and adult immature/ETP-ALL subclass and identified a rare but recurrent t(2;14)(q22;q32) translocation in a few of these typical ETP-ALL cases. This novel translocation, results in juxtaposition of the promotor and proximal portion of the ​BCL11B locus to the ​ZEB2 locus, a finding reminiscent of previously described ​BCL11B-driven T-ALL oncogene activation. These data are strongly indicative for an oncogenic driver role for  ​ZEB2in T-ALL, and is consistent with previously reported retroviral mutagenesis screens  that have suggested ​Zeb2 involvement in leukaemogenesis. Whether or not loss/alternative functions of ​ BCL11B are involved in leukaemia initiation/progression specifically in these patients remains unknown. Importantly, other mechanisms are involved in ETP-ALL patients leading to ​ZEB2upregulated expression levels besides these rare recurrent translocations. One potential mechanism may be related to altered expression of  ​miR200c, which have previously been shown to negatively regulate Zeb family member expression and to be altered in cancer settings. Exactly how  ​miR200c levels are downregulated to begin with remains to be determined but may be related to changes in the promoter methylation status as has been previously shown in other tumour types.

Using a ​ROSA26-based overexpression of ​Zeb2 in the endothelium and throughout the entire haematopoietic system induces formation of precursor T-cell lymphoblastic leukaemia. Using the T-cell-restricted  ​CD4-Cre line to overexpress ​Zeb2 recapitulated the spontaneous thymoma formation and strongly suggests a cell autonomous role of ​Zeb2, however, given the paracrine effects associated with ​Zeb2 deletion in the central nervous system, they cannot exclude environmental involvement in the observed T-cell lymphoma formation phenotype. Intercrossing onto a ​p53-deficient background drastically accelerated tumour formation and shifted the tumour spectrum towards an immature precursor T-cell lymphoblastic leukaemia, with an expression profile similar to ETP-ALL patients. Mouse tumours showed prototypical activating mutations affecting ​Notch1 and loss of the tumour-suppressor genes ​Pten and ​Ikzf1, supporting the fact that the ​p53 null ​Zeb2 transgenic mouse model closely recapitulates human T-cell leukaemia, and is in keeping with the higher occurrence of ​IKZF1 mutations in ETP-ALLs.

In line with a presumed ETP-ALL phenotype for the mouse ​Zeb2-driven leukaemias, they also observed increased LSC properties. These enhanced LSC characteristics associated with ​Zeb2 overexpression are in line with previous observations that expression of the ZEB family members is correlated with poor prognosis of solid tumours, putatively in part through the acquisition of enhanced cancer stemness programmes.

Mechanistically, we demonstrate that ​ZEB2 leads to upregulated ​IL7R expression in immature/ETP-ALL cells. A strong positive correlation was observed between ​Zeb2 and ​Il7r mRNA levels in our mouse model and in the human LOUCY cell line, which exhibits an ETP-ALL-like phenotype. ​IL-7signalling is of key importance in normal thymocyte maturation and differentiation and constitutive activation of ​IL7R-driven signalling has been shown to lead to T-ALL oncogenesis. In approximately 10% of T-ALLs, including ETP-ALLs, activating mutations in the ​IL7R gene are present representing an interesting drugable target for novel treatment using ​IL7R-blocking antibodies or more novel compounds for the inhibition of downstream JAK/​STAT5 signalling27, like ​RUX. Previous studies have demonstrated that use of blocking ​IL-7 antibodies or use of ​IL-7-deficient mice could dramatically decrease human T-ALL formation in xenotransplantation settings using immunocompromised mice27, 42. Here we could see a clear ​IL-7-dependent survival effect of the derived ​Zeb2-overexpressing mouse T-ALL cell lines in vitro and an effect on their ability to initiate secondary tumours after transplantation. Whether the described ​ZEB2-​IL7R axis is also important in human ETP-ALL disease progression remains to be tested.

In conclusion, we have found that sustained overexpression of ​Zeb2 acts as a leukaemic driver for immature T-ALLs with increased leukaemic stem cell properties. ​ZEB2-mediated upregulation of Il7rexpression and activation of the JAK/STAT pathway represents a possible therapeutic target for this aggressive and chemoresistant subtype of human T-ALL.

Reference

ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and ​IL-7 receptor signaling, Nature Communications 6, Article number: 5794 ｜doi:10.1038/ncomms6794