Acute lymphoblastic leukaemia (ALL) is the most common form of cancer in children worldwide. Subtypes of paediatric ALL carrying rearrangements of the mixed lineage leukaemia (MLL) gene shows a dismal prognosis. The mechanisms of how gene fusions relate to disease transformation remain to be fully explained. MLL fusions have the potential to impact the RNA processing of genes at genome scale through changes in transcriptional elongation, thereby providing a potential new layer of molecular variation that has remained undetected so far and which could lead to new prognostic markers and therapeutic strategies. We present here an exhaustive analysis of the RNA-processing alterations in infant ALL samples in relation to MLL-r.
We detected a significant overexpression of multiple splicing factors (SFs) conserved across MLL-r cases and distinct to other common rearrangements like MBNL1, which was previously found upregulated in infant MLL-r ALL and has been proposed as a potential therapeutic target associated.
We have initially tested this result by performing cytotoxicity assays with clinically relevant splicing-modulating compounds using in vitro models and patient derived cells of MLL-r ALL. In particular H3B-8800, a compound that is in Phase I clinical trials for adult leukaemia, showed a potent and homogeneous effect across all cell models tested.
In agreement with these findings, we found common and specific splicing events that are differentially spliced between MLL-r samples and controls. These findings indicate that splicing is generally altered in childhood acute leukaemia and represents a novel therapeutic opportunity.