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

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.