Epigenetic Modifiers as Therapeutic Targets in Pediatric T-cell Acute Lymphoblastic Leukemia

Background:

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Approximately 15% of newly diagnosed ALL cases in children arise from dysfunctional T-cells. T-cell ALL (T-ALL) patients are historically linked with a poor prognosis. We have shown in a mouse model that T-cells lacking Dnmt3a, an enzyme that establishes the DNA methylation epigenetic mark, show reduced differentiation capacity and are more susceptible to cancer development in a NOTCH1-driven model of T-ALL.

Project Goal:

We propose that mutation of Dnmt3a predisposes T-cells to become cancerous. In T-ALL patients, DNMT3A mutations are strongly associated with NOTCH1 mutations and confer a dismal prognosis.

In our ALSF project, we have been characterizing the function of Dnmt3a in T-cell development and

evolving T-ALL. Recent work from other studies have highlighted a role for histone demethylase enzymes in T-ALL pathogenesis, and we note abnormal histone marks in DNMT3A-mutant T-ALL. Here, we will characterize the response of T-ALL cell lines to histone demethylase inhibitors, and the influence of DNMT3A in this sensitivity. This could lead to development of a new class of therapeutic agents for this specific subset of T-ALL patients.