B-cell acute lymphoblastic leukaemia (B-ALL) is the most common cancer in children and the second most prevalent acute leukemia in adults. B-ALL comprises a vast number of different molecular subtypes, which are dramatically different in terms of long-term survival and usually carry oncogenic gene translocations. However, these oncogenic mutations in B-cell progenitors are not sufficient to generate overt leukaemia and instead initiate a clonal, pre-malignant state that requires secondary mutations to develop the disease. Particularly, mutations in the B-lymphoid factor PAX5 occur in 30% of all B-ALL cases. PAX5 is the major regulator of normal B-cell development and a key haploinsufficient tumor suppressor in B-ALL. In human and mouse B-ALL, reconstitution of PAX5 physiological levels induces leukaemia regression, which, together with the high frequency of PAX5 monoallelic mutations in B-ALL, open a unique window for reinforcing the functions of the Pax5Wt allele and thus bypass its haploinsufficiency in B-ALL. However, despite the functional relevance of PAX5, very little is known on how it is regulated, and no upstream regulators have been described so far. In this sense, the work of our lab, currently under review, has identified a regulatory mechanism of PAX5 by a member of the family NAD+-dependent deacetylases known as Sirtuins, that play a key role in the response to stress. This mechanism therefore represents a first-in-class rationale to rescue PAX5 tumor suppressor functions in B-ALL. The overall goal of this project is to dissect the ability of Sirtuins to enhance PAX5 tumor suppressor functions in B-ALL and its potential as a novel therapeutic strategy for this disease. To address this goal, we propose a multidisciplinary approach including molecular and cellular biology techniques in combination with genomics and in vivo patient-derived xenografts.

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