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 5

Jab1 transcriptionally regulates IGF2BP3 to control m6A modification and stability of LILRB4 mRNA.

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Jab1 transcriptionally regulates IGF2BP3 to control m6A modification and...
(A) Venn diagram showing the overlap between genes identified from Jab1 knockdown RNA-Seq, c-JUN ChIP-Seq, and known RBPs, highlighting IGF2BP3 as a candidate. (B) Radar plot depicting correlation of candidate genes with Jab1 expression in AML samples from the GSE12662 dataset. (C) Jab1 knockdown alters the expression of several m6A regulatory factors in MOLM13 cells, with IGF2BP3 showing the most notable reduction. (D) ChIP-qPCR reveals c-JUN binding enrichment at the IGF2BP3 promoter, suggesting transcriptional regulation of IGF2BP3 by Jab1 through c-JUN. TSS, transcription start site. (E) RNA-Seq analysis shows that LILRB4 is one of the most significantly downregulated genes following IGF2BP3 knockdown in MOLM13 cells. (F) Western blot validation confirms that Jab1 knockdown reduces IGF2BP3 protein levels and that IGF2BP3 silencing leads to reduced LILRB4 expression. (G) Actinomycin D chase assay shows that IGF2BP3 knockdown accelerates LILRB4 mRNA decay, indicating its role in mRNA stabilization. (H) MeRIP-Seq metagene analysis shows m6A peak distribution across transcripts and identifies the conserved GGACU motif in MOLM13 cells treated with CSN5i-3. CDS, coding sequence. (I and J) Pie and Venn diagrams display the proportion and overlap of m6A-modified RNA species in MOLM13 cells following CSN5i-3 treatment. (K) Western blot validation of specific bands in cell lysates and IGF2BP3-RIP complexes, evaluating the effectiveness of RIP products. (L) RIP-qPCR analysis quantifies enrichment of LILRB4 in IGF2BP3 and m6A immunoprecipitates, confirming IGF2BP3 binding to m6A-modified LILRB4 mRNA.