Xpo1-KO Mouse

XPO1, also known as Exportin 1 or chromosome region maintenance protein 1, is a crucial export receptor. It is responsible for the nuclear-cytoplasmic transport of hundreds of proteins and multiple RNA species, thus playing a vital role in maintaining cellular homeostasis [1,2,3]. It is involved in the nucleocytoplasmic transport pathway, which is tightly regulated in eukaryotic cells [2].

In cancer research, elevated levels of XPO1 and recurrent mutations have been reported in multiple cancers. For example, in acute myeloid leukemia (AML), the XPO1 inhibitor selinexor activates PI3Kγ-dependent AKT signaling by upregulating the purinergic receptor P2RY2 [4]. In pancreatic ductal adenocarcinoma (PDAC), the combination of the XPO1 inhibitor selinexor with gemcitabine-nab-paclitaxel synergistically inhibited tumor growth in the KPC mouse model, re-organized the tumor stromal architecture, and suppressed proliferation [5]. In chronic lymphocytic leukaemia (CLL), XPO1 inhibition enhances NK cell effector function against primary CLL cells [6]. In B cell hematological malignancies, molecular alterations in the XPO1 gene, like the E571K mutation hotspot, have been identified and may serve as a minimal residual disease tool [7].

In conclusion, XPO1 is essential for the proper nuclear-cytoplasmic partitioning of large molecules. Model-based research, especially in mouse models for various cancers, has revealed its oncogenic role in multiple malignancies. Understanding XPO1's functions through these models provides potential therapeutic strategies for treating cancer patients.

References:

1. Azizian, Nancy G, Li, Yulin. 2020. XPO1-dependent nuclear export as a target for cancer therapy. In Journal of hematology & oncology, 13, 61. doi:10.1186/s13045-020-00903-4. https://pubmed.ncbi.nlm.nih.gov/32487143/

2. Kim, Ekaterina, Mordovkina, Daria A, Sorokin, Alexey. . Targeting XPO1-Dependent Nuclear Export in Cancer. In Biochemistry. Biokhimiia, 87, S178-S70. doi:10.1134/S0006297922140140. https://pubmed.ncbi.nlm.nih.gov/35501995/

3. Azmi, Asfar S, Uddin, Mohammed H, Mohammad, Ramzi M. 2020. The nuclear export protein XPO1 - from biology to targeted therapy. In Nature reviews. Clinical oncology, 18, 152-169. doi:10.1038/s41571-020-00442-4. https://pubmed.ncbi.nlm.nih.gov/33173198/

4. Lin, Kevin H, Rutter, Justine C, Xie, Abigail, Puissant, Alexandre, Wood, Kris C. 2022. P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia. In Nature cancer, 3, 837-851. doi:10.1038/s43018-022-00394-x. https://pubmed.ncbi.nlm.nih.gov/35668193/

5. Uddin, Md Hafiz, Al-Hallak, Mohammad Najeeb, Khan, Husain Yar, Shields, Anthony F, Azmi, Asfar S. . Molecular analysis of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in KPC pancreatic cancer mouse model. In Clinical and translational medicine, 13, e1513. doi:10.1002/ctm2.1513. https://pubmed.ncbi.nlm.nih.gov/38131168/

6. Fisher, Jack G, Doyle, Amber D P, Graham, Lara V, Khakoo, Salim I, Blunt, Matthew D. 2023. XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression. In Leukemia, 37, 2036-2049. doi:10.1038/s41375-023-01984-z. https://pubmed.ncbi.nlm.nih.gov/37528310/

7. Camus, Vincent, Miloudi, Hadjer, Taly, Antoine, Sola, Brigitte, Jardin, Fabrice. 2017. XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy. In Journal of hematology & oncology, 10, 47. doi:10.1186/s13045-017-0412-4. https://pubmed.ncbi.nlm.nih.gov/28196522/