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 6

Jab1 inhibition by CSN5i-3 suppresses AML progression and prolongs survival in PDX models.

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Jab1 inhibition by CSN5i-3 suppresses AML progression and prolongs survi...
(A) CSN5i-3 treatment reduces intracellular ROS levels in patient-derived AML cells (AML#11) in a dose-dependent manner, as assessed by flow cytometry. (B and C) CSN5i-3 significantly decreases cell viability and increases apoptosis in multiple primary AML samples (AML#13, #15, and #16) after 24–48 hours of treatment (n = 3 per group, by unpaired 2-tailed Student’s t test). (D) Schematic overview of the PDX model: patient-derived AML cells were transplanted into NCG mice and expanded for secondary xenografting, followed by CSN5i-3 treatment (100 mg/kg/d, 14 days). FCM, flow cytometry. (E and F) Gross organ examination and statistical analysis show reduced spleen size and weight in CSN5i-3–treated mice, with no significant changes in liver or kidney (n = 5 per group, by unpaired 2-tailed Student’s t test). (G) Kaplan-Meier survival curves indicate that CSN5i-3 treatment significantly prolongs survival in mice engrafted with AML#12 and AML#16 cells (Kaplan-Meier analysis with log-rank test). (H) Wright-Giemsa staining reveals reduced leukemic infiltration in bone marrow (BM) of CSN5i-3–treated mice (original magnification × 1,000; n = 5 per group, by unpaired 2-tailed Student’s t test). (I) Serum levels of liver (ALT and AST) and kidney (CREA and BUN) function markers remain unaffected by CSN5i-3 (n = 5 per group, by unpaired 2-tailed Student’s t test). ALT, alanine aminotransferase; AST, aspartate aminotransferase; CREA, creatinine; BUN, blood urea nitrogen. (J) Immunohistochemical staining of bone marrow further demonstrates reduced expression of human CD45, CD33, Jab1, and LILRB4 in CSN5i-3–treated mice (n = 5 per group, by unpaired 2-tailed Student’s t test).