Interferon gamma (IFNy) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNy levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNy producing T and NK cells, high IFNy signaling, and immunosuppressive features. IFNy signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNy treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNy score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNy is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.

Bofei Wang, Patrick K. Reville, Mhd Yousuf Yassouf, Fatima Z. Jelloul, Christopher Ly, Poonam N. Desai, Zhe Wang, Pamella Borges, Ivo Veletic, Enes Dasdemir, Jared K. Burks, Guilin Tang, Shengnan Guo, Araceli Isabella Garza, Cedric Nasnas, Nicole R. Vaughn, Natalia Baran, Qing Deng, Jairo Matthews, Preethi H. Gunaratne, Dinler A. Antunes, Suhendan Ekmekcioglu, Koji Sasaki, Miriam B. Garcia, Branko Cuglievan, Dapeng Hao, Naval Daver, Michael R. Green, Marina Konopleva, Andrew Futreal, Sean M. Post, Hussein A. Abbas