Ilaria Iacobucci, PhD
Department of Pathology, St. Jude Children's Research Hospital
In this edition of Grand Rounds in Hematology and Oncology from April 2023, Ilaria Iacobucci, PhD, a scientist leading the pathology division at St. Jude Children’s Research Hospital, Memphis, Tennessee, presents an extensive overview of her research into high-risk acute leukemias, including myeloid and lymphoid subtypes in children and adults. In this 56-minute presentation, Dr. Iacobucci focuses on elucidating the genomic landscape of these malignancies through bulk and single-cell sequencing, identifying genetic drivers, and developing functional models to explore targeted therapies. She highlights the importance of molecular characterization for subclassifying leukemias and informing treatment strategies.
Dr. Iacobucci’s research has contributed to refining the classification of acute leukemias, particularly by identifying new genomic subtypes of acute lymphoblastic leukemia and mixed-phenotype acute leukemia, which are now incorporated into recent international classification schemes. Her team has also defined distinct subtypes of acute erythroid leukemia (AEL), a rare and aggressive form of leukemia, through integrative genomic profiling.
Using CRISPR-Cas9 gene editing and single-cell sequencing, her group demonstrated that combinations of mutations—particularly in TP53, splicing factors, and epigenetic regulators—determine lineage identity and clonal evolution. They showed that early mutations like those in DNMT3A or TET2 often predate transformation events and drive leukemogenesis when combined with secondary hits.
Importantly, Dr. Iacobucci’s work identifies potential therapeutic vulnerabilities in AEL. Cells with TP53 mutations show sensitivity to PARP inhibitors and hypomethylating agents, while NUP98 fusion-driven leukemias respond to menin inhibitors. She also demonstrates that BCL-XL is a key dependency in erythroid leukemia cells, and targeting this protein, especially in combination with JAK2 inhibitors, may offer a promising therapeutic strategy.
Dr. Iacobucci advocates integrating genetic profiling into routine clinical evaluation to better stratify risk and guide therapy, especially for under-recognized and difficult-to-treat entities like AEL.