2. Academic Validation
  3. FUBP3 mediates MXI1 stability to silence RRAS and hinder MAPK signaling in acute megakaryoblastic leukemia progression

FUBP3 mediates MXI1 stability to silence RRAS and hinder MAPK signaling in acute megakaryoblastic leukemia progression

  • Cancer Immunol Immunother. 2025 Dec 22;75(1):23. doi: 10.1007/s00262-025-04257-z.
Ying Zhu # 1 2 3,  Jinying Liu # 4,  Jiqiang Zeng 2,  Zhirui Liu 5,  Zhimin Yan 6,  Shanrong Zhang 7,  Huixi Luo 8,  Zhipeng Wu 7,  Jiawei Lu 7,  Fang Qiu 9 10 11,  Junsong Ye 12 13 14 15 16,  Chen Lu 17
Affiliations

Affiliations

  • 1 Department of Blood Transfusion, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
  • 2 School of Medical Technology, Gannan Medical University, No. 1, Medical College Road, Ganzhou, 341000, Jiangxi, People's Republic of China.
  • 3 Ganzhou Key Laboratory of Transfusion Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China.
  • 4 Basic Medical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
  • 5 State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, People's Republic of China.
  • 6 Department of Hematopathology, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
  • 7 The First Clinical Medical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
  • 8 School of Nursing, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
  • 9 Department of Blood Transfusion, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China. [email protected].
  • 10 School of Medical Technology, Gannan Medical University, No. 1, Medical College Road, Ganzhou, 341000, Jiangxi, People's Republic of China. [email protected].
  • 11 Ganzhou Key Laboratory of Transfusion Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China. [email protected].
  • 12 Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China. [email protected].
  • 13 School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China. [email protected].
  • 14 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China. [email protected].
  • 15 Key Laboratory for Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China. [email protected].
  • 16 Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China. [email protected].
  • 17 School of Medical Technology, Gannan Medical University, No. 1, Medical College Road, Ganzhou, 341000, Jiangxi, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 41428087 DOI: 10.1007/s00262-025-04257-z
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.

Keywords

Acute megakaryoblastic leukemia; CD8+ T cells; FUBP3/MXI1; MAPK signaling; RRAS.

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