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Bmi1 (B-lymphoma Mo-MLV insertion region 1) is essential for self-renewal of cancer stem cells and is frequently upregulated in various cancer cells.  Bmi1/Ring1 complex is the catalytic core of the Polycomb Repressive Complexes 1(PRC1) that is a key player in ubiquitination of histone H2A, which affects gene expression pattern involved in various cellular processes, including cell proliferation, growth, DNA repair, apoptosis and senescence.

Overexpression of Bmi1 often correlates with advanced stages of disease, aggressiveness, poor prognosis and resistance to radiation and chemotherapy. Moreover, BMI1+ cancer stem cells (CSCs) are enriched in head and neck squamous cell carcinoma (HNSCC) after cisplatin plus anti-PD1 treatment as a mechanism of immunotherapy resistance. Pharmacological and genetic inhibition of BMI1 eliminated BMI1+ CSCs and prevented HNSCC relapses.



Further reading

Alchanati et al., The E3 ubiquitin-ligase Bmi1/Ring1A controls the proteasomal degradation of Top2alpha cleavage complex - a potentially new drug target (2009). PLoS One 4(12):e8104

Su et al., The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression (2019). Cancer Cell 36(2):139-55

Jia et al., BMI1 Inhibition Eliminates Residual Cancer Stem Cells after PD1 Blockade and Activates Antitumor Immunity to Prevent Metastasis and Relapse (2020). Cell Stem Cell. 27(2):238-53

Geng and Gao, Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms (2020). Int. J. Mol. Sci. 21, 8594


Cbl-b (Casitas B lymphoma-b), a RING finger E3 ubiquitin ligase that functions as a negative regulator of T-cell stimulation responses, and is essential for establishing the threshold for T-cell activation and for regulating peripheral T-cell tolerance through various mechanisms. Blocking Cbl-b activates both adaptive (T cells) and innate (NK cells) anti-tumor responses leading to tumor destruction. Moreover, Cbl-b knockout mice spontaneously reject tumors, making it a genetically validated novel intracellular checkpoint target for immuno-oncology.



Further reading

Loeser et al., Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells (2007). J Exp Med.  204(4):879-91

Paolino, M. et al., Essential role of E3 ubiquitin ligase activity in Cbl-b–regulated T cell functions (2011).  Journal of Immunology 186, 2138-2147

Lutz-Nicoladoni, C. et al., Modulation of immune cell functions by the E3 ligase Cbl-b (2015). Frontiers in Oncology 5, 58

Shifrut et al., Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function (2018). Cell 175(7):1958-71

Tang et al., Regulation of immune responses by E3 ubiquitin ligase Cbl-b (2019). Cell Immunol. 340:103878

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