Acute Lymphoblastic Leukemia (ALL) is an aggressive blood cancer with survival rates of only 50%. Especially high-risk and relapsed disease cases present with poor prognoses. Current frontline therapy includes DNA damaging chemotherapy and glucocorticoids. However, as only 15-20% of all relapsed ALL cases present with new genetic alterations, various non-genetic mechanisms have arisen recently at the forefront of therapy research. Among these, splicing, the process of intron removal and stitching coding exons into mature transcripts is perturbed in T-cell ALL (T-ALL). Notably, even in the absence of splicing factor mutations, T-ALL patients present with broadly disrupted splicing landscapes. This happens through aberrant regulation of splicing factors (SF) via posttranslational modifications, with levels of SFs significantly elevated in high-risk T-ALL cases. We and others have shown that transcripts involved in apoptosis and programmed cell death, are among the most commonly misspliced in cancer, and splicing inhibition enhances the apoptosis-inducing potential of BCL2 inhibitors. In this project, we aim at unraveling the molecular mechanisms of splicing aberrations in T-ALL and assess their downstream impact on apoptosis-related transcripts. We will explore the potential of pro-apoptotic and splicing-targeting drug combinations to enhance tumor cell death in preclinical settings. Our work will lay the foundation for novel therapeutic treatments for high-risk T-ALL.