SETD2 Mutations in Prognosis and Chemotherapy Resistance in Relapsed Acute Lymphoblastic Leukemia
Despite substantial improvements in the treatment of pediatric acute lymphoblastic leukemia, relapse still occurs in 15% of children and 50% of infants, with particular subgroups at substantially higher risk. In contrast to newly diagnosed ALL, patients with relapsed ALL have substantially worse rates of long term survival, reflecting the acquisition of or selection for leukemia cells with chemotherapy resistance. Recurrent mutations found in leukemias at relapse are likely associated with chemotherapy resistance, and targeting them may potentially reverse or prevent the development of resistance.
Next generation sequencing of samples from pediatric ALL patients identified an enrichment of mutations in genes known as epigenetic regulators, at relapse. One of these epigenetic regulators, SETD2, has mutations in 10% of patients which frequently led to its inactivation. Inactivating SETD2 in an ALL cell line led to substantial resistance to 6-mercaptopurine, a commonly used chemotherapy agent in ALL. Importantly, SETD2 activity, and thus chemotherapy sensitivity, has the potential to be restored by targeting KDM4A, a gene that inhibits SETD2. This proposal explores the hypothesis that SETD2 inactivation leads to chemotherapy resistance and increased relapse risk in pediatric acute lymphoblastic leukemia.
The expected outcome of this work is the identification of a novel risk factor and a potentially targetable mechanism of chemotherapy resistance in pediatric acute lymphoblastic leukemia. The ultimate goal of this line of study would be to reverse or prevent chemotherapy resistance in patients with acute lymphoblastic leukemia.
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