Work

CBFB-MYH11 directly activates TGFβ and PD-L1 to drive immune evasion in acute myeloid leukemia

Year: 2026

Type: article

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.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-016242