Medical and health sciences
- Cell signalling
- Cancer biology
- Cancer therapy
Cure rates in children with T-cell acute lymphoblastic leukemia (T-ALL) approach 90%, due to intensive chemotherapy protocols with glucocorticoids as core components. However, the outcome for patients that fail to obtain a complete hematologic remission upon induction therapy or suffer from relapse remains extremely poor. Upon treatment with chemotherapy, tumor cells tend to acquire survival mechanisms that cause drug resistance. To this end, we aim to gain detailed insight into these mechanisms in order to develop targeted therapies, that will reduce the risk for relapse.
Previously, we have identified IL7 as a critical mediator of T-ALL progression and survival in phenotypically immature T-ALLs, from the ETP-ALL, TLX+ and HOXA+ subtypes. These IL7Rhigh patients activated STAT5/PIM1 signaling, making them sensitive towards PIM inhibition, which synergized with glucocorticoid treatment. However, only a subset of patients would benefit from this treatment. Here, we obtained preliminary evidence for an important role of active IL4 signaling in phenotypically mature T-ALLs from the NKX2.1/2+ and TAL/LMO+ subtypes. Moreover, some of these T-ALLs acquire the ability for autocrine IL4 production, in contrast to their normal T-cell counterparts. Given all this, we believe that IL4 signaling is critical for survival in immunophenotypically more mature T-ALLs, rendering leukemias less sensitive towards current chemotherapy. Therefore, we aim to characterize IL4R inhibition as a novel therapeutic strategy in the treatment of T-ALL.