This prestigious research grant was awarded to Luca for his research project proposal dissecting the molecular mechanisms driving resistance to therapies in acute myeloid leukemia.

Luca Tottone, Ph.D is Assistant Scientist in Nimer Lab at the Sylvester Comprehensive Cancer Center, University of Miami and distinguished member of Miami Scientific Italian Community.

Dr. Tottone is a senior scientist with 10+ years of hands-on research experience conducting in vivo and in vitro pre-clinical and translational studies in the field of oncology and blood malignancies, with particular focus on acute leukemias. In T-cell acute lymphoblastic leukemia (T-ALL), Dr. Tottone has dissected the epigenetic mechanisms and the genetic alterations that alter the expression of oncogenes and tumor suppressors by affecting the activity of their enhancers, particular regions of the genome that tune the expression of the genes. Specifically, Dr. Tottone has revealed that the leukemogenic mechanism undergoing Notch3 overexpression in T-ALL rely on a NOTCH-P300-JMJD3 axis regulating Notch3 levels through an intronic enhancer. Additionally, Dr. Tottone has discovered the first ever reported tumor suppressor enhancer of PTEN, and revealed that deletions of this enhancer occurring in T-ALL patients promote leukemia development and progression.

Thanks to the results of his studies, Dr. Tottone was awarded with several intramural, state, and national grants and received several scientific honors.

Overview – In Nimer Lab, at the NCI Sylvester Comprehensive Cancer Center, we study the molecular mechanisms regulating normal hematopoiesis and the alterations that ultimately lead to Acute Myeloid Leukemia (AML) onset, resistance to therapies and cancer relapse. In this context, we have previously demonstrated the essential role of CARM1 in sustaining the generation of leukemias of myeloid origin and AML progression. CARM1 is a methyltransferase, overexpressed in AML, that regulates the activity of a wide range of proteins and oncogenes through the asymmetric dymethylation of their arginine residues. Our preliminary results show that silencing CARM1 in AML reads out in the reduction of the expression of MYC-dependent genes, suggesting that CARM1 directly controls c-MYC activity in AML. c-MYC is an undruggable, hard to target oncogene, that in AML promotes leukemia proliferation, therapy resistance and long-term relapse by sustaining leukemic cells survival and immunity escape. In this research proposal we provide evidence of a mutual oncogenic loop of regulation between CARM1 and c-MYC, where c-MYC promotes CARM1 gene expression and, in turn, CARM1 sustains c-MYC transcriptional activity (a CARM1 – MYC axis). By affecting CARM1 levels and activity in cellular and mouse leukemic models, we intend to demonstrate that CARM1 represents a promising therapeutic target to tackle resistance to therapies and prevent AML relapse.