CBFB-MYH11 directly activates TGFβ and PD-L1 to drive immune evasion in acute myeloid leukemia
9 affiliations
- 1Department of Stomatology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
- 2Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- 3Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, People's Republic of China
- 4Department of Medicine, Division of Hematology/Oncology, Augusta University, Augusta, Georgia, USA
- 5Department of Biochemistry and Molecular Biology, Augusta University Medical College of Georgia, Augusta, Georgia, USA
- 6Immunology Center of Georgia, Augusta University, Augusta, Georgia, USA
- 7Charlie Norwood VA Medical Center, Augusta, Georgia, USA
- 8Department of Biostatistics, Data Science and Epidemiology, Augusta University, Augusta, Georgia, USA
- 9Oncogenesis and Development Section, Division of Intramural Research, National Human Genome Research Institute, Bethesda, Maryland, USA
Abstract
Background: Core binding factor acute myeloid leukemia (CBF-AML) driven by the CBFB-MYH11 fusion oncogene is associated with high initial remission rates, yet 30%–50% of patients ultimately relapse. While immune evasion is a recognized hallmark of leukemia progression, the precise mechanisms orchestrated by the CBFB-MYH11 oncogene remain poorly understood. Furthermore, the role of transforming growth factor-beta (TGFβ) in hematological malignancies is highly controversial, often viewed as a tumor suppressor in early hematopoiesis rather than a driver of immune evasion.
Methods: We used an inducible Cbfb-MYH11 knock-in mouse model and primary AML cell transplantation to profile the immune microenvironment during leukemogenesis. We integrated flow cytometry, bulk and single-cell RNA sequencing (scRNA-seq), CUT&RUN, luciferase reporter assay, ChIP-qPCR, and ChIP-Seq. Functional in vitro T-cell suppression assays and in vivo engraftment using Pdcd1 knockout (PD-1 KO) mice, and treatments with the anti-PD-L1 antibody, TGFβ receptor inhibitor galunisertib, and cytarabine were performed to evaluate immunotherapeutic vulnerabilities.
Results: Leukemogenesis in the Cbfb-MYH11 model was accompanied by profound T-cell suppression and exhaustion, and the AML cells effectively inhibited T-cell proliferation in co-culture. Transcriptomic profiling identified marked upregulation of Cd274 (PD-L1) and Tgfb1 in AML cells. Mechanistically, CUT&RUN and ChIP-Seq demonstrated that the CBFβ-SMMHC fusion oncoprotein and its co-factor RUNX1 directly bind to the promoter regions of CD274 and TGFB1 to transcriptionally activate their expression in both murine and human AML models. While genetic ablation of PD-1 in host mice provided only limited survival benefits, pharmacological blockade of TGFβ effectively restored T cell function and delayed AML progression. Importantly, combining cytarabine with galunisertib provided superior disease control, reversed T cell exhaustion, and significantly prolonged survival compared with chemotherapy alone, which can be further enhanced by targeting PD-L1/PD-1.
Conclusions: The CBFB-MYH11 oncogene directly orchestrates an immunosuppressive microenvironment by transcriptionally activating PD-L1 and TGFβ. These findings provide more insight into the role of TGFβ in CBF-AML, establishing it as a primary, tumor-derived immunosuppressor directly driven by the fusion oncogene. This provides a strong mechanistic rationale for incorporating TGFβ blockade into standard chemotherapy and immune checkpoint blockade regimens to restore anti-leukemic immunity and prevent relapse.
Related
- Single-cell and bulk transcriptome-based identification of myeloid-derived suppressor cell-associated immune evasion signatures and a prognostic model for gastric cancer.
- Biologically Informed Multi-Omics Integration Reveals Clinically Meaningful Patient Representations in Acute Myeloid Leukemia
- Non-genetic remodeling drives leukemia propagation and reveals actionable vulnerabilities in acute myeloid leukemia
- An unusual case of basophilic meningitis revealing a chronic-phase chronic myeloid leukemia: a report after almost three years of follow-up.
- CSE1L enrichment in pediatric and young adult acute myeloid leukemia reveals a ribosomal export dependency
BibTeX
@article{fang2026cbfbmyh11,
title = {{CBFB-MYH11 directly activates TGFβ and PD-L1 to drive immune evasion in acute myeloid leukemia}},
author = {Hui Fang and Chang Liu and Xiaocui Lu and Ting Zhang and Xuexiu Fang and Stephanie F Mori and Miao Yu and Qimei Han and Yoonah Ruby and Gavin Wang and Daniel Peters and Litao Zhang and Huidong Shi and Kebin Liu and Jorge Cortes and Haocheng Ding and Paul Liu and Bo Cheng and TianXiang Hu},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-016242},
url = {https://doi.org/10.1136/jitc-2026-016242},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - CBFB-MYH11 directly activates TGFβ and PD-L1 to drive immune evasion in acute myeloid leukemia
AU - Hui Fang
AU - Chang Liu
AU - Xiaocui Lu
AU - Ting Zhang
AU - Xuexiu Fang
AU - Stephanie F Mori
AU - Miao Yu
AU - Qimei Han
AU - Yoonah Ruby
AU - Gavin Wang
AU - Daniel Peters
AU - Litao Zhang
AU - Huidong Shi
AU - Kebin Liu
AU - Jorge Cortes
AU - Haocheng Ding
AU - Paul Liu
AU - Bo Cheng
AU - TianXiang Hu
PY - 2026
DA - 2026/10/26
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-016242
UR - https://doi.org/10.1136/jitc-2026-016242
AB - Background: Core binding factor acute myeloid leukemia (CBF-AML) driven by the CBFB-MYH11 fusion oncogene is associated with high initial remission rates, yet 30%–50% of patients ultimately relapse. While immune evasion is a recognized hallmark of leukemia progression, the precise mechanisms orchestrated by the CBFB-MYH11 oncogene remain poorly understood. Furthermore, the role of transforming growth factor-beta (TGFβ) in hematological malignancies is highly controversial, often viewed as a tumor suppressor in early hematopoiesis rather than a driver of immune evasion. Methods: We used an inducible Cbfb-MYH11 knock-in mouse model and primary AML cell transplantation to profile the immune microenvironment during leukemogenesis. We integrated flow cytometry, bulk and single-cell RNA sequencing (scRNA-seq), CUT&RUN, luciferase reporter assay, ChIP-qPCR, and ChIP-Seq. Functional in vitro T-cell suppression assays and in vivo engraftment using Pdcd1 knockout (PD-1 KO) mice, and treatments with the anti-PD-L1 antibody, TGFβ receptor inhibitor galunisertib, and cytarabine were performed to evaluate immunotherapeutic vulnerabilities. Results: Leukemogenesis in the Cbfb-MYH11 model was accompanied by profound T-cell suppression and exhaustion, and the AML cells effectively inhibited T-cell proliferation in co-culture. Transcriptomic profiling identified marked upregulation of Cd274 (PD-L1) and Tgfb1 in AML cells. Mechanistically, CUT&RUN and ChIP-Seq demonstrated that the CBFβ-SMMHC fusion oncoprotein and its co-factor RUNX1 directly bind to the promoter regions of CD274 and TGFB1 to transcriptionally activate their expression in both murine and human AML models. While genetic ablation of PD-1 in host mice provided only limited survival benefits, pharmacological blockade of TGFβ effectively restored T cell function and delayed AML progression. Importantly, combining cytarabine with galunisertib provided superior disease control, reversed T cell exhaustion, and significantly prolonged survival compared with chemotherapy alone, which can be further enhanced by targeting PD-L1/PD-1. Conclusions: The CBFB-MYH11 oncogene directly orchestrates an immunosuppressive microenvironment by transcriptionally activating PD-L1 and TGFβ. These findings provide more insight into the role of TGFβ in CBF-AML, establishing it as a primary, tumor-derived immunosuppressor directly driven by the fusion oncogene. This provides a strong mechanistic rationale for incorporating TGFβ blockade into standard chemotherapy and immune checkpoint blockade regimens to restore anti-leukemic immunity and prevent relapse.
SN - 2051-1426
ER -