3168 – INVESTIGATING THE ROLE OF THE KDM4A LYSINE DEMETHYLASE IN PEDIATRIC ACUTE MYELOID LEUKEMIA

Abstract

In Canada, almost one third of childhood cancers are leukemias. Encouragingly, many of these pediatric leukemias are now treatable with a variety of anti-cancer drugs. Nonetheless, leukemia still accounts for an alarming ∼25% of cancer-related deaths in children. The goal of therapy against leukemia is to kill malignant cells while sparing normal hematopoietic stem and progenitor cells (HSPC). Recent research has revealed multiple events occurring at the genome level that promote transformation of HSPC. These events include genetic alterations (DNA mutations, chromosomal translocations), as well as epigenetic modifications, leading to alteration of the gene expression pattern of HSPC. Interestingly, genes coding for epigenetic regulators are frequently mutated, deleted or amplified in leukemia. We have identified that a specific chromatin modifier, the lysine demethylase KDM4A, is overexpressed in pediatric MLL-AF9 acute myeloid leukemia, and plays essential roles for the proliferation and survival of leukemic cells, but dispensable for normal HSPC. The main objective of the proposed research project is to decipher the precise molecular mechanisms by which this epigenetic regulator promotes progression of pediatric AML using innovative cellular, molecular, genetic, and pharmacological approaches. The proposed studies have great potential to not only allow a better understanding of molecular events underlying pediatric AML, but also identify effective drugs for combatting childhood blood cancer that is still plagued with dismal survival rates.