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Project Topic
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Background: Despite recent promising therapeutic responses, relapse/refractoriness in acute myeloid (AML), B-cell acute lymphoblastic (B-ALL) leukemias and chronic myeloid leukemia in blast phase (CML-BP) remain medical unmet needs. Recent data also from our ERA PerMed MEET-AML project, demonstrates that more than individual genomic alterations, such as mutations, deletions, translocation of oncogenic fusion genes, the 3D genome organization of leukemic cell results in oncogene activation. The disrupted dynamic chromatin interactions, particularly through Topologically Associated Domain (TAD) boundary loss and, consequently, gene de-regulation, represent a new mechanism of leukemogenesis.
Hypothesis: TAD disruption could be a major mechanism of leukemogenesis with potential involvement in leukemia stem-cell metabolic reprogramming and targetable vulnerability. In this regard, the pathologic expression of new leukemic transcripts could generate unexpected drug sensitivity and drug combinatory hypotheses for cancer vulnerability.
Aims: We aim to elucidate how the disruption of TAD boundaries, potentially driven by DNA lesions as chromosome rearrangements, deletion, or mutations can alter the expression of metabolism-related genes, thus identifying metabolic vulnerabilities to be targeted by innovative therapeutic combinations in AML, B-ALL, and CML-BP. Moreover, we aim to set up a drug sensitivity screening platform for the study of novel combination therapies targeting these vulnerabilities.
Methods: By multi-omics analysis including innovative techniques like Hi-C and long-read sequencing, associated with an individual drug sensitivity screening platform, we will investigate TAD hijacking events and their impact on the regulation of oncogenes and genes involved in leukemic cell metabolism in adult AML, B-ALL, and CML-BP patients. By computational methods, these omics data will be integrated with the high throughput ex vivo drug sensitivity test (on a newly developed translational microscopy-based model, an ex vivo single-cell drug screening platform) of combinations of FDA-approved drugs or metabolism-related drugs and the most promising vulnerabilities will be validated by functional studies.
Expected results and impact: Focusing on subgroups developing resistance to standard therapies, and based on in vitro drug sensitivity assay and by “in silico” identification of potential metabolic leukemic targets, associated with TAD disruption and deregulated transcripts, TOSCANINI is expected to provide the scientific community with a novel approach for expanding the field of combination therapies and, mainly, to identify new therapeutic approaches in difficult-to-cure leukemic patients. TOSCANINI project will be able to address new hypothesis of combinatory treatments in an exploratory clinical trial that could be translated to the clinical practice.
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