Objectives/Goals: To determine how loss of sympathetic nerves and β2-adrenergic receptor (Adrb2) signaling remodels the leukemic bone marrow niche, alters immune responses against leukemia, and influences acute myeloid leukemia (AML) progression. Methods/Study Population: AML was modeled using MLL-AF9-driven murine leukemia and human AML xenografts (MOLM-13 and patient-derived samples) in NOD scid gamma (NSG) mice. Sympathetic signaling was disrupted chemically with 6-hydroxydopamine or genetically using Adrb2 knockout mice. Leukemic burden, survival, and immune composition were analyzed by flow cytometry and imaging. Public RNA-seq and clinical datasets were used to assess ADRB2 expression and its prognostic value in AML patients. Results/Anticipated Results: AML induces sympathetic neuropathy in both mouse and human bone marrow. Denervation or Adrb2 loss accelerated AML and reduced survival in immune-competent mice, correlating with decreased CD8 + T cell activity. In contrast, denervation reduced leukemia burden in immunodeficient NSG mice, and β2-adrenergic agonist treatment enhanced AML proliferation in vitro . High ADRB2 expression in AML patients predicted worse survival, particularly in M5/MLL-rearranged subtypes. Discussion/Significance of Impact: Sympathetic signaling exerts dual roles in AML, supporting immune surveillance but directly acting on leukemic cells to promote AML progression. These findings identify β2-adrenergic signaling as a potential therapeutic target, especially in immunodeficient or chemotherapy-treated AML patients.
Begum et al. (Wed,) studied this question.