Rational Therapeutic Targeting of Oncogenic Immune Signaling States in Myeloid Malignancies

Treating acute myeloid leukemia (AML) remains challenging in part because of the plasticity of the cells that make up this type of cancer. Although one treatment strategy is to target the various dysregulated immune and inflammatory pathways commonly found in AML, the therapeutic benefit of this approach is modest because of the heterogenous nature of these cells. Daniel Starczynowski is leading a group of investigators aiming to target a potential master regulator of dysregulated immune and inflammatory pathways in AML. The target is UBE2N, an enzyme involved in the ubiquitin-proteasome system that acts as the quality control machinery of the cell. The investigators have discovered that inhibiting UBE2N modulates many immune/inflammatory pathways simultaneously and severely limits the fitness of AML cells. They are following up this finding by developing and refining small molecule inhibitors of UBE2N, which they will test in AML models to better understand these signaling pathways and lay the groundwork for treatment that has the potential to be beneficial to a larger number of patients.