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

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.  DNA methylation is a modification to DNA that does not alter the DNA sequence, but can act with genetic mutations in cancer. DNA methylation introduces marks or "flags" to genes. The exact pattern of methylation flags can turn certain genes on and off. Cancer cells exhibit an altered pattern of these methylation flags, but we do not know how these patterns become changed in cancer cells, or how to reverse it. We have shown in a mouse model that T-cells lacking Dnmt3a, an enzyme that establishes methylation flags, show reduced differentiation capacity and are more susceptible to T-ALL development. We propose that mutation of Dnmt3a predisposes T-cells to become cancerous. However, as many groups have failed to correlate altered DNA methylation patterns with DNMT3A mutations in patients, we hypothesize that DNMT3A-mutation T-ALL is caused by DNA methylation-independent mechanisms.

This work could lead to a paradigm-shift by viewing other molecules as the effectors of DNMT3A-mutation pathology. Although outcomes for T-ALL patients have improved with intensive chemotherapy, such regimens have significant side effects. The design of tumor-specific therapies is a main goal of current research efforts. We envision this work will lead to the development of directed therapies for high-risk T-ALL pediatric patients who have a high likelihood of treatment failure or have suffered relapse.