Abstract 3961: CBFβ-SMMHC directly activates immune regulatory genes to establish a global immune suppression in mouse AML model
Authors: Hui Fang, Xiaocui Lu, Chang Liu, Xuexiu Fang, Stephanie Fay Mori, Bo Cheng, John K Cowell, Tianxiang Hu
Journal: Cancer Research (2025)

Abstract A recurrent inversion involved in chromosome 16 leads to the fusion of genes CBFB and MYH11, which encodes CBFβ-SMMHC fusion protein acting as a driving factor of acute myeloid leukemia (AML). Though breakthroughs have been made in the treatment of leukemia, drug resistance and relapse post treatment are still major causes of adverse prognosis of AML patients. It’s found that an immune suppressive microenvironment usually affects the treatment response of cancer patients, therefore, a better understanding of the immune microenvironment holds the promise of developing novel therapy to improve outcomes. We investigated dynamic shifts in the immune landscape as leukemia progresses in the conditional Cbfb-MYH11 knockin mouse model. Accompanying the continuous increase of cKit+ leukemia cells, all the other immune cells dramatically dropped with the progression of AML. Notably, a significant reduction occurred in the levels of immune effector T, B, and NK cells. The presence of myeloid-derived suppressor cells (MDSCs) also decreased during leukemogenesis. This immune suppression phenomenon was consistently observed in both primary leukemia induction and following leukemia cell transplantation. When co-cultured with CD4 T cells, the cKit+ leukemia cells significantly inhibited the division of T cells. Mechanistically, RNA-Seq profiling revealed a global activation of the immunosuppressive pathway genes including PDL1, Tgfβ1, and Nfkb1 in these leukemia cells. Consistently, Cbfb-MYH11 inhibitor treatment can attenuate the inhibitive effects of AML cells on T cell proliferation, due to the reduced expression of immune suppressive genes. Correlative analysis in AML patient samples also confirmed the positive correlations between the immune suppression genes and MYH11. Furthermore, flow cytometry revealed that PD-L1 was exclusively upregulated in cKit+ leukemia cells, accompanied by increased CD4 and CD8 T cell exhaustion, suggesting that the PD-L1/PD1 pathway at least partially contributes to this global immune suppression. Indeed, transplantation of the same leukemia cells into PD1 KO mice led to delayed AML progression. Taken together, our results reveal the establishment of a global immune suppression in this AML mouse model by the immune suppressive AML cells expressing CBFβ-SMMHC, and immune suppressive pathways including PD-L1/PD1 are involved, justifying a combinational treatment of immunotherapy with current “7+3” regimen for treatment of AML carrying CBFβ-SMMHC. Citation Format: Hui Fang, Xiaocui Lu, Chang Liu, Xuexiu Fang, Stephanie Fay Mori, Bo Cheng, John K Cowell, Tianxiang Hu. CBFβ-SMMHC directly activates immune regulatory genes to establish a global immune suppression in mouse AML model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3961.