Abstract

Myeloid leukemia is a malignant hematologic disorder characterized by abnormal proliferation and differentiation arrest of myeloid progenitor cells, and its molecular mechanisms remain incompletely understood. Protein 4.1R (EPB41) is a cytoskeleton-associated protein that exhibits tumor-suppressive effects in various cancers; however, its function and underlying mechanism in myeloid leukemia remain unclear. Our results demonstrated that knockdown of Protein 4.1R significantly promoted cell proliferation, inhibited apoptosis, and increased the proportion of S-phase cells in K562 and HEL cells. Transcriptome sequencing identified the long non-coding RNA CCDC26 as a key downstream molecule. RNA pull-down and nuclear-cytoplasmic fractionation experiments further confirmed that Protein 4.1R directly binds CCDC26 in the nucleus and limits its export to the cytoplasm. Mechanistically, this interaction suppressed CCDC26-mediated activation of the Mitogen-Activated Protein Kinase (MAPK) pathway in the cytoplasm, thereby exerting tumor-suppressive effects and inhibiting the progression of myeloid leukemia. In summary, this study elucidates a mechanism by which Protein 4.1R inhibits MAPK signaling through regulation of CCDC26 nuclear-cytoplasmic transport, providing a theoretical framework for understanding the molecular pathology of leukemia and identifying potential therapeutic targets.