Jab1 promotes immune evasion and progression in acute myeloid leukemia models under oxidative stress
Nan Zhang, Qian Wang, Guopeng Chen, Li Liu, Zhiying Wang, Linlu Ma, Yuxing Liang, Jinxian Wu, Xinqi Li, Xiaoyan Liu, Fuling Zhou
Nan Zhang, Qian Wang, Guopeng Chen, Li Liu, Zhiying Wang, Linlu Ma, Yuxing Liang, Jinxian Wu, Xinqi Li, Xiaoyan Liu, Fuling Zhou
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Research Article Cell biology Hematology

Jab1 promotes immune evasion and progression in acute myeloid leukemia models under oxidative stress

Abstract

Acute myeloid leukemia (AML) is the most common hematological malignancy. Leukemia stem cells exhibit high levels of oxidative stress, with ROS being the primary products of this stress, inducing the expression of c-JUN activation domain-binding protein 1 (Jab1). Previous studies have demonstrated that Jab1, as a transcriptional coactivator of c-JUN, promotes the malignant progression of AML under oxidative stress. However, its role in immune evasion is still under investigation. Here, we observed that knocking out Jab1 reduced the expression of immune checkpoints in vivo, effectively overcoming the immune evasion of AML. Interestingly, the deletion of Jab1 had no impact on the maturation of normal hematopoietic cells in mice. Mechanistically, Jab1 directly activated IGF2BP3 by driving the transcription factor c-JUN, consequently modulated the m6A modification of LILRB4 mRNA, and promoted immune evasion in AML. Finally, CSN5i-3 effectively disrupted the signaling pathway mediated by Jab1, thereby restoring cellular immune surveillance and halting the progression of AML. Thus, our results highlight the functional role of Jab1 in supporting AML survival and support the development of targeted therapeutic strategies.

Authors

Nan Zhang, Qian Wang, Guopeng Chen, Li Liu, Zhiying Wang, Linlu Ma, Yuxing Liang, Jinxian Wu, Xinqi Li, Xiaoyan Liu, Fuling Zhou

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Figure 4

Jab1 stabilizes LILRB4 mRNA and promotes immune evasion in AML.

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Jab1 stabilizes LILRB4 mRNA and promotes immune evasion in AML. (A–C) Tr...
(A–C) Transcriptomic analysis in MOLM13 cells with Jab1 knockdown reveals significant changes in gene expression, enriched in immune-related Gene Ontology terms and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways including cytokine signaling and leukocyte activation. (D) RT-qPCR validation confirms downregulation of LILRB4 upon Jab1 depletion, while PD-L1, PD-L2, and other LILRB family members remain largely unchanged (n = 3 per group, by unpaired 2-tailed Student’s t test). (E) Relative expression levels of PDL1, PDL2, and LILRB4 in TCGA-AML (n = 151) and OHSU-AML (n = 451) datasets (by unpaired 2-tailed Student’s t test). (F) Univariate Cox regression shows high LILRB4 expression is associated with poorer overall survival in AML (P = 0.0003). (G and H) CSN5i-3, a Jab1 inhibitor, reduces cell viability in multiple AML cell lines and downregulates LILRB4 protein expression in a dose-dependent manner. (I–K) Coculture of CSN5i-3–pretreated AML cells with PBMCs enhances LILRB4 suppression and promotes T cell–mediated leukemia lysis across multiple effector/target ratios (n = 3 per group, by unpaired 2-tailed Student’s t test). (L) ChIP-qPCR analysis of c-JUN transcription factor binding motifs and LILRB4 promoter sequence to detect enrichment of LILRB4 in c-JUN complexes. TSS, transcription start site. (M) Assessment of LILRB4 mRNA stability and half-life in Jab1 knockdown MOLM13 and MV411 cells treated with 5 μg/mL actinomycin D at 0, 2, 4, and 6 hours.