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Acute lymphoblastic leukaemia: from San Raffaele a study that could improve prognosis and therapy
Acute lymphoblastic leukaemia (ALL) is the most frequent tumour in paediatric age (it accounts for 80% of all leukaemia and 25% of all cancers diagnosed between 0 and 14 years of age). It originates from particular white blood cells, the lymphocytes, and is characterised by an accumulation of these cells in the bone marrow, blood and other organs.
From San Raffaele comes a study that elucidates the molecular mechanism underlying this subtype of leukaemia and, thanks to information obtained with advanced sequencing and transcriptomic technologies, will help to identify further prognostic criteria at an early stage and better tailor treatments for this pathology.
The research - recently published in Science Advances - was coordinated by Davide Gabellini, group leader of the Gene Expression Regulation laboratory
San Raffaele study
Our cells contain transcription factors, i.e. proteins that bind to specific DNA sequences and regulate gene expression. In the case of B-cell acute lymphoblastic leukaemia, in about 10% of cases the disease is caused by a 'rearranged' form of the transcription factor DUX4 called DUX4-r. To date, the molecular mechanism by which DUX4-r causes leukaemia is poorly understood and no therapeutic strategies are available to specifically target this type of leukaemia.
"By combining transcriptomics and genomics approaches, we found that although DUX4 and DUX4-r share a common DNA binding site, they bind to and activate different sets of genes. In particular, only DUX4-r activates the expression of genes involved in cell adhesion, migration and cancer,' says Gabellini.
We also found that DUX4-r activity is strictly dependent on a transcriptional coactivator called GTF2I, which is highly expressed in B cells. Specifically, genetic or pharmacological inhibition of GTF2I blocks the leukaemogenic activity of DUX4-r in both cellular and animal models of this leukaemia. Overall, our results demonstrate that DUX4-r acquires its oncogenic capacity through a gain of interaction with GTF2I, which is the key to activating genes required for leukaemia'.
Future studies will focus on a better understanding of the molecular mechanisms controlling GTF2I activity and expression in order to develop personalised therapeutic strategies for DUX4-r-driven leukaemia.