Enhancer plasticity sustains oncogenic transformation and progression of B-Cell Acute Lymphoblastic leukemia.

Corleone, G.; Sorino, C.; Caforio, M.; Di Giovenale, S.; De Nicola, F.; Bertaina, V.; Pitisci, A.; Cortile, C.; Locatelli, F.; Folgiero, V.; Fanciulli, M.

doi:10.1101/2022.05.18.492497

bioRxiv · 10.1101/2022.05.18.492497

Enhancer plasticity sustains oncogenic transformation and progression of B-Cell Acute Lymphoblastic leukemia.

Corleone, G.·Sorino, C.·Caforio, M.·Di Giovenale, S.·De Nicola, F.·Bertaina, V.·Pitisci, A.·Cortile, C.·Locatelli, F.·Folgiero, V.·Fanciulli, M.

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Abstract

Growing evidence report that non-genetic-driven events such as enhancer reprogramming promote neoplastic transformation and strongly contribute to the phenotypical heterogeneity of cancers as much as genetic variation. In this context, we investigated the role of enhancers in sustaining oncogenic transformation in B-Cell Acute Lymphoblastic leukemia in children (BCP-ALL), a type of cancer caused by the accumulation of lymphoid progenitor cells in the bone marrow and a leading cause of cancer-related mortality in children. Using next-generation sequencing (ATAC-seq), we built the most up-to-date map of chromatin accessibility in pediatric BCP-ALL. We observed that enhancer activity dynamically changes during cancer progression and represents principal phenomena underlying phenotypic-functional characteristics of BCP-ALL progression. BCP-ALL patients are dominated by a regulatory repertoire (N=[~]11k) originally represented at diagnosis that shrinks under treatments and subsequently re-expands, driving the relapse. We then deployed a wide range of in-vivo, in-vitro assays, and in-silico analyses to demonstrate the impact of enhancer activity in determining the phenotypical complexity. CRISPR-Cas-9-mediated validation of selected productive enhancers demonstrated a high capability of these regions to control MYB and DCTD oncogenic activities. Taken together, these findings provide direct support to the notion that enhancer plasticity is a crucial determinant of the BCP-ALL phenotype.

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Corleone, G., Sorino, C., Caforio, M., Di Giovenale, S., De Nicola, F., Bertaina, V., Pitisci, A., Cortile, C., Locatelli, F., Folgiero, V., Fanciulli, M.. 2022-05-19. Enhancer plasticity sustains oncogenic transformation and progression of B-Cell Acute Lymphoblastic leukemia.. https://doi.org/10.1101/2022.05.18.492497

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