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FUBP3 mediates MXI1 stability to silence RRAS and hinder MAPK signaling in acute megakaryoblastic leukemia
Ying Zhu1,2,3, Jinying Liu4, Jiqiang Zeng2
1Department of Blood Transfusion, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
Abstract:
RRAS, a gene encoding a small monomeric GTPase that controls cell adhesion and migration, has been linked to leukemogenesis. However, its function in acute megakaryoblastic leukemia (AMKL), a rare type of acute myeloid leukemia, remains indistinct. Here, we explored the potential and mechanism of RRAS in the immune escape of AMKL. Human AMKL cells M-07e and UT-7 were infected using lentiviruses and co-cultured with CD8+ T cells. An AMKL mouse model was constructed by tail vein injection of the mouse AMKL cells with genetic intervention. RRAS expression and ERK-1/2 phosphorylation were enhanced, and MXI1 was reduced in M-07e and UT-7 cells. RRAS knockdown and MXI1 or FUBP3 overexpression inhibited AMKL cell viability and promoted the anti-tumor immunity of CD8+ T cells and apoptosis of AMKL cells. Knockdown of RRAS or overexpression of FUBP3 decreased the infiltration and aggregation of megakaryocytes in the bone marrow, liver, and spleen of AMKL mice, which were rescued by MXI1 knockdown or RRAS overexpression. MXI1 inhibited the MAPK signaling by recruiting NCOR1/2, Sin3A/B, and HDAC1 to co-repress RRAS transcription. FUBP3 stabilized MXI1 to block RRAS-mediated ERK signaling. Overall, we provide evidence of an unrevealed axis FUBP3/MXI1/RRAS/MAPK in the CD8+ T cell immunity in AMKL.
Insights
This study reveals how RRAS (Ras-related protein 4A) contributes to immune evasion in acute megakaryoblastic leukemia (AMKL). Targeting the FUBP3/MXI1/RRAS/MAPK pathway can enhance anti-tumor immunity in AMKL.
Area of Science:
- Molecular Biology
- Immunology
- Oncology
Background:
- Ras-related protein 4A (RRAS) is implicated in leukemogenesis but its role in acute megakaryoblastic leukemia (AMKL) is unclear.
- Understanding RRAS function is crucial for developing novel AMKL therapies.
Purpose of the Study:
- To investigate the role and mechanism of RRAS in AMKL immune escape.
- To elucidate the FUBP3/MXI1/RRAS/MAPK signaling axis in AMKL.
Main Methods:
- Utilized lentiviral infection of human AMKL cell lines (M-07e, UT-7) and co-culture with CD8+ T cells.
- Established a genetically modified AMKL mouse model for in vivo studies.
- Assessed gene expression, protein phosphorylation, cell viability, apoptosis, and immune cell infiltration.
Main Results:
- RRAS expression and ERK-1/2 phosphorylation were elevated, while MXI1 was reduced in AMKL cells.
- RRAS knockdown or FUBP3/MXI1 overexpression reduced AMKL cell viability and boosted CD8+ T cell anti-tumor immunity.
- Modulating RRAS, FUBP3, or MXI1 affected megakaryocyte infiltration in AMKL mice.
- MXI1 suppressed MAPK signaling by recruiting co-repressors to RRAS, and FUBP3 stabilized MXI1.
Conclusions:
- Identified a novel FUBP3/MXI1/RRAS/MAPK pathway regulating CD8+ T cell immunity in AMKL.
- This axis represents a potential therapeutic target for enhancing anti-leukemic immune responses.
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