Reactive Oxygen Species-Mediated c-Jun Activation Domain-Binding Protein-1 (Jab1) Promotes Immune Escape in Hyperleukocytic Acute Myeloid Leukemia

Background: Hyperleukocytic acute myeloid leukemia (HL-AML) is a group of clonal hematopoietic stem cell diseases. Our previous studies have confirmed that Jab1 mediated by reactive oxygen species (ROS) plays a role in the pathogenesis of AML as a transcription coactivator of AP-1/JUN. Here, we reveal the specific regulatory mechanism of immune escape in HL-AML by Jab1, which serves as a new therapeutic target for HL-AML.

Methods: The relationship between Jab1 expression and immune cell subtypes in clinical bone marrow samples were analyzed by RT-qPCR. Lentiviral knockout of Jab1 was combined with transcriptomics and chromatin co-precipitation to evaluate the transcriptional regulatory mechanisms involved, and bioinformatics to identify molecular interactions. The changes of each immunophenotype were analyzed by flow cytometry.

Results: Compared with healthy controls and AML, Jab1 was highly expressed in HL-AML and was associated with a poor prognosis. However, in HL-AML patients, the proportion of CD8+ T cells was significantly decreased, while the proportion of regulatory T cells was slightly increased, and the secretion of cytokines IL-2, IL-4, IFN-γ, and IFN-α decreased. In H₂O₂-induced oxidative stress, ROS levels promote the entry of c-Jun into the nucleus, while Jab1 knockdown blocks c-Jun nuclear expression and transcriptional activity. Mechanically, Jab1 regulates leukemic immunosuppressive target LILRB4 rather than PDL1/PDL2. As a coactivator of transcription factor c-Jun, Jab1 cannot directly regulate the transcription of LILRB4 but enhances the stability of LILRB4 mRNA. By high-throughput screening, it was found that N6-methyladenosine modification directly recognized the LILRB4 mRNA site. Finally, it was concluded that Jab1/IGF2BPs/LILRB4 signal axis was involved in disease progression in HL-AML.

Conclusions: We provided compelling evidence to demonstrate that Jab1 under oxidative stress is associated with tumorigenesis and poor prognosis of AML, which can serve as a target to develop therapeutics for cancer treatment.

No relevant conflicts of interest to declare.