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
View: Text | PDF
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

×

Figure 2

Jab1 facilitates immune evasion and sustains leukemia progression in MLL-AF9–driven AML.

Options: View larger image (or click on image) Download as PowerPoint
Jab1 facilitates immune evasion and sustains leukemia progression in MLL...
(A) Schematic representation of the experimental workflow for generating the MLL-AF9 AML mouse model and subsequent Jab1 knockdown using shRNA lentiviral vectors. (B) Western blot verifies effective Jab1 knockdown in leukemic cells. (C) Survival analysis shows that Jab1 silencing significantly prolongs survival in AML-bearing mice (Kaplan-Meier analysis with log-rank test). (D) In vivo bioluminescence imaging reveals reduced leukemic burden in Jab1-knockdown groups across multiple time points (days 14–35 after transplantation). (E) Wright-Giemsa staining shows decreased leukemic infiltration in peripheral blood (PB) and bone marrow (BM) of Jab1-deficient mice; original magnification, ×1,000. (F) Jab1 knockdown leads to increased body weight and reduced splenomegaly, indicating alleviated disease severity (n = 5 per group, by unpaired 2-tailed Student’s t test). (G–I) Flow cytometry shows that Jab1 knockdown leads to a significant reduction of GFP+ leukemic cells and LSCs (GFP+Gr-1–c-Kit+) in the bone marrow and spleen, while no significant difference was observed in the peripheral blood (n = 5 per group, by unpaired 2-tailed Student’s t test). (J) T cell proliferation, as measured by Ki-67 expression, is enhanced in CD4+ and CD8+ T cells upon Jab1 depletion in leukemic mice (n = 5 per group, by unpaired 2-tailed Student’s t test). (K and L) Jab1 silencing significantly reduces the proportion of PD-1+ and LAG-3+ exhausted CD4+ and CD8+ T cells in the spleen (n = 5 per group, by unpaired 2-tailed Student’s t test).