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 3

Jab1 is dispensable for normal hematopoiesis and multilineage reconstitution.

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Jab1 is dispensable for normal hematopoiesis and multilineage reconstitu...
(A) Generation of conditional Jab1-knockout mice (Mx1-Cre Jab1fl/fl) using poly(I:C)-induced recombination; successful deletion in c-Kit+ HSPCs was verified by Western blot. (B–E) Peripheral blood analysis shows no significant differences in leukocyte subtypes (WBC, lymphocyte [LYM], monocyte [MON], neutrophil [NEU], eosinophil [EOS], and basophil [BASO]), RBC count, hemoglobin (Hb), or platelet (PLT) levels among WT, Jab1-HET, and Jab1-KO mice (n ≥ 6 per group, by unpaired 2-tailed Student’s t test). (F) Schematic diagram of classical hematopoietic lineage differentiation. (G) Flow cytometry of peripheral blood reveals comparable proportions of myeloid cells, B cells, CD4+ T cells, and CD8+ T cells across all genotypes (n ≥ 6 per group, by unpaired 2-tailed Student’s t test). (H) Quantification of bone marrow progenitor and stem cell populations (LSK, LK, CMP, GMP, MEP, CLP, HSCs, and MPP1–MPP5) shows no significant disruptions in Jab1-deficient mice (n ≥ 6 per group, by unpaired 2-tailed Student’s t test). (I) Total bone marrow cell counts and spleen weights were not affected by Jab1 deletion, further supporting preserved hematopoiesis (n ≥ 6 per group, by unpaired 2-tailed Student’s t test). (J and K) Secondary competitive bone marrow transplantation assays demonstrate that Jab1-KO HSCs maintain long-term reconstitution capacity, with comparable CD45.2+ donor-derived contributions to all major blood lineages (myeloid, B, CD4+, and CD8+ T cells) up to 16 weeks after transplantation (primary transplantation results are shown in Supplemental Figure 9, C–I) (n ≥ 6 per group, by unpaired 2-tailed Student’s t test).