MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) is largely (if not solely) driven by inappropriate epigenetic events, and is most efficiently targeted by epigenetic-based drugs, including DNA demethylating agents, histone deacetylase (HDAC) inhibitors, inhibitors of BET bromodomain proteins, or inhibition of the histone methyltransferase DOT1L. However, leukemic cells have shown to readily acquire resistance to epigenetic-based drugs. Epigenetic plasticity allows leukemic cells to swiftly remodel their regulatory pathways, losing their dependency on the targeted epigenetic component and acquiring dependencies on alternative regulatory programs. My research aims to identify common regulatory pathways exploited by MLL-rearranged ALL cells to evade susceptibility to epigenetic-based drugs, and find therapeutic strategies that effectively block these escape routes, and thereby eliminating resistance to promising epigenetic-based therapies for MLL-rearranged infant ALL.
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