Elucidating the Role of N-Myc in a High-risk Pediatric T Cell Leukemia
Background: Acute lymphoblastic leukemia (ALL) is the most frequent tumor diagnosed in children. Although many efficient therapies are available to treat ALL, there are specific subtypes of the disease that either do not respond to the drugs or tend to relapse after an initial response. Among these difficult subtypes is the Early T-cell Progenitor Acute Lymphoblastic Leukemia (ETP-ALL), an ALL caused by an alteration of the T-lymphocyte progenitor cells. The mechanism that makes ETP-ALL, among all acute leukemias, so difficult to treat is still unknown. While analyzing the blood samples of children with acute leukemia, we observed that those affected by the ETP-ALL subtype had an abnormally high expression of the Mycn gene. This gene encodes for a protein (N-myc) that regulates cell growth and is critical for brain development. An excessive N-myc expression has been observed in brain tumors, therefore we considered that a similar mechanism might drive ETP-ALL as well.
Project Goal: To test this hypothesis, we will study mice affected by a leukemia comparable to human ETP-ALL and investigate if the ablation of N-myc will make their leukemia regress. At the same time, we will transplant patient-derived ETP-ALL cells into recipient mice and treat them with drugs targeting N-myc. This set of experiments will allow us to see if the inhibition of N-myc is a promising therapy for ETP-ALL patients. In parallel, we will accurately analyze the molecular changes induced by N-myc aberrant expression to better understand what drives this disease and what makes it so difficult to treat.
Project Update 2021: In spite of recent advancements in the treatment of T cell Acute Lymphoblastic Leukemia (T-ALL), some patients still don’t respond to standard therapies and have frequent relapses. These tumors are defined as high-risk and require a higher dose of chemotherapy, which unfortunately carries heavier side effects. Early T cell Progenitor Acute Lymphoblastic Leukemia (ETP-ALL) is an example of leukemia that is more resistant to standard treatment, and the reasons are still largely unknown. With this study, our group was able to better characterize a large group of ETP-ALL patients both from a genetic and an epigenetic point of view. We discovered that the high-risk patients had an unusually elevated expression of an oncogene (N-Myc) and of a nearby – and never described before –epigenetic element (Nmre). We characterized the interaction of the oncogene and the epigenetic element by multiple experiments both in cell lines and in living organisms and we discovered a possible vulnerability mechanism for ETP-ALL maintenance. Moreover, the interaction observed between these two elements inspired us to analyze the epigenetic structure of ETP-ALL at a broader level. We then discovered that these patients, compared to lower-risk leukemic patients and to healthy individuals, display particular changes in the conformation of their DNA. This analysis revealed new elements that are typical of ETP-ALL, and therefore offers us new interesting targets for a more effective and less toxic way of treating high-risk patients.
