Acute lymphoblastic leukemia (ALL) is the most common cancer in children. A subgroup with T-cell ALL (T-ALL) have a poor prognosis. DNA methylation is an “epigenetic” modification that does not alter the DNA sequence, but produces marks or “flags” on DNA that can turn genes on or off. Cancer cells exhibit an altered pattern of these methylation flags. As mutations in DNMT3A, an enzyme that establishes methylation flags, have been discovered in T-ALL patients, we propose that DNMT3A mutations predispose T-cells to become cancerous. We have shown that mice lacking Dnmt3a are more susceptible to T-ALL development. Moreover, immature T-cells in the thymus of mice lacking Dnmt3a have an overactive pathway called Notch. These studies will investigate the links between Dnmt3a-mediated DNA methylation, Notch, and ALL.
Aims: 1) Determine why the Notch1 pathway is activated in immature T cells in mice lacking Dnmt3a; 2) Investigate if loss of Dnmt3a lowers the threshold for malignant transformation of these immature T-cells; 3) Determine if NOTCH1 signaling is activated in DNMT3A-mutation pediatric T-ALL patients
Potential impact: The long-term goal is to help develop targeted therapeutics for patients with DNMT3A-mutation-driven cancers. We envision this work leading to the development of targeted epigenetic therapies for high-risk T-ALL pediatric patients and lead to improved outcomes.