PROJECT SUMMARY Acute myeloid leukemia (AML) is defined as a clonal expansion of abnormal myeloid blasts which are impaired to differentiate into mature and functional myeloid cells. Toll-like receptors (TLRs) are pathogen- associated molecular pattern (PAMP) receptors that specialize in recognizing foreign pathogens and elicit an innate immune response through promoting myeloid cell differentiation and inflammatory cytokine production. The role of TLR signaling in AML is poorly understood, and the mechanisms involved in an innate immune response through TLRs, and whether this induces differentiation and/or cell death of AML blasts is unclear. Two of the most commonly mutated genes in AML are FLT3 and DNMT3A, where 20% of AML patients can be found with co-occurring mutations, which results in a poor prognosis. Preliminary data indicate that TLRs are expressed on the surface of AML cells, and stimulation of these receptors produces a proinflammatory response associated with AML blast differentiation. In sum, I identify, in DNMT3A-mutant AML, a TLR signaling network that regulates differentiation of AML and increases the survival of this common and clinically poor AML subtype which can lead to a prospectively new differentiating/therapeutic agent for AML treatment.