Journal for immunotherapy of cancer
CBFB-MYH11 directly activates TGFβ and PD-L1 to drive immune evasion in acute myeloid leukemia
By Fang H, Liu C, Lu X and 16 others.
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.