{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T23:59:01Z","timestamp":1781135941470,"version":"3.54.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":58,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["1R01CA205247"],"award-info":[{"award-number":["1R01CA205247"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA33572"],"award-info":[{"award-number":["P30CA33572"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The small GTPase RAN plays a role in the biogenesis of mature miR-126, which is supplied by the bone marrow arterioles to leukemic stem cells (LSCs). MiR-126 supports the homeostasis of LSCs that initiate and maintain acute myeloid leukemia (AML). While therapeutic targeting of RAN has been difficult due to its structural features, through molecular dynamics simulations and docking studies, we have identified MAR-3.6.2 as a novel allosteric inhibitor that binds in a cryptic pocket in the C-terminal domain of RAN. We showed that MAR-3.6.2 disrupted RAN interaction with its guanine nucleotide exchange factor RCC1 and prevented the nuclear switch of RAN-GDP to RAN-GTP. This in turn led to RAN nuclear retention and reduced the RAN\/XPO5-mediated export of pre-miR-126, thereby limiting mature miR-126 biogenesis in endothelial cells and their exogenous supply of mature miR-126 to LSCs. In a Mll\n                    <jats:sup>PTD\/WT<\/jats:sup>\n                    \/Flt3\n                    <jats:sup>ITD\/ITD<\/jats:sup>\n                    AML murine model, MAR-3.6.2 reduced leukemia burden, prolonged survival, and decreased LSC frequency in secondary transplants. These findings highlight MAR-3.6.2 and future, potential derivatives as a promising small molecule-based approach to eradicate AML LSCs via inhibition of RAN\/XPO5 trafficking and block of miR-126 biogenesis.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-10026-0","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T04:33:55Z","timestamp":1776141235000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Allosteric inhibition of RAN decreases miR-126 biogenesis in endothelial cells and controls acute myeloid leukemia growth"],"prefix":"10.1038","volume":"9","author":[{"given":"Melissa","family":"Valerio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyuan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunjun","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4653-7797","authenticated-orcid":false,"given":"Ning","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0483-2149","authenticated-orcid":false,"given":"Supriyo","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3911-5262","authenticated-orcid":false,"given":"Weidong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5285-0088","authenticated-orcid":false,"given":"Lianjun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinh Hoa","family":"Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9968-2360","authenticated-orcid":false,"given":"Jia","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4703-7524","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9889-3502","authenticated-orcid":false,"given":"J. Jefferson P.","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8100-8132","authenticated-orcid":false,"given":"Nagarajan","family":"Vaidehi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-0861","authenticated-orcid":false,"given":"Le Xuan Truong","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3983-5908","authenticated-orcid":false,"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"10026_CR1","doi-asserted-by":"publisher","first-page":"345","DOI":"10.3389\/fcell.2020.00345","volume":"8","author":"Z Boudhraa","year":"2020","unstructured":"Boudhraa, Z., Carmona, E., Provencher, D. & Mes-Masson, A. M. Ran GTPase: a key player in tumor progression and metastasis. Front Cell Dev. Biol. 8, 345 (2020).","journal-title":"Front Cell Dev. Biol."},{"key":"10026_CR2","doi-asserted-by":"publisher","unstructured":"El-Tanani, M. et al. Ran GTPase and its importance in cellular signaling and malignant phenotype. Int. J. Mol. Sci. 24, https:\/\/doi.org\/10.3390\/ijms24043065 (2023).","DOI":"10.3390\/ijms24043065"},{"key":"10026_CR3","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/nrd.2016.139","volume":"15","author":"JML Ostrem","year":"2016","unstructured":"Ostrem, J. M. L. & Shokat, K. M. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat. Rev. Drug Discov. 15, 771\u2013785 (2016).","journal-title":"Nat. Rev. Drug Discov."},{"key":"10026_CR4","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1038\/nm.4499","volume":"24","author":"B Zhang","year":"2018","unstructured":"Zhang, B. et al. Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia. Nat. Med. 24, 450\u2013462 (2018).","journal-title":"Nat. Med."},{"key":"10026_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26420-7","volume":"12","author":"L Zhang","year":"2021","unstructured":"Zhang, L. et al. Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance. Nat. Commun. 12, 6154 (2021).","journal-title":"Nat. Commun."},{"key":"10026_CR6","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13045-021-01133-y","volume":"14","author":"B Zhang","year":"2021","unstructured":"Zhang, B. et al. Treatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AML. J. Hematol. Oncol. 14, 122 (2021).","journal-title":"J. Hematol. Oncol."},{"key":"10026_CR7","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/j.devcel.2008.07.008","volume":"15","author":"JE Fish","year":"2008","unstructured":"Fish, J. E. et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev. Cell 15, 272\u2013284 (2008).","journal-title":"Dev. Cell"},{"key":"10026_CR8","doi-asserted-by":"publisher","first-page":"14405","DOI":"10.1074\/jbc.270.24.14405","volume":"270","author":"SA Richards","year":"1995","unstructured":"Richards, S. A., Lounsbury, K. M. & Macara, I. G. The C terminus of the nuclear RAN\/TC4 GTPase stabilizes the GDP-bound state and mediates interactions with RCC1, RAN-GAP, and HTF9A\/RANBP1. J. Biol. Chem. 270, 14405\u201314411 (1995).","journal-title":"J. Biol. Chem."},{"key":"10026_CR9","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1021\/acs.biochem.4c00484","volume":"64","author":"W Wei","year":"2025","unstructured":"Wei, W. et al. Disordered C-terminus plays a critical role in the activity of the small GTPase ran. Biochemistry 64, 1393\u20131404 (2025).","journal-title":"Biochemistry"},{"key":"10026_CR10","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1021\/ci400750x","volume":"54","author":"H Li","year":"2014","unstructured":"Li, H., Kasam, V., Tautermann, C. S., Seeliger, D. & Vaidehi, N. Computational method to identify druggable binding sites that target protein\u2013protein interactions. J. Chem. Inf. Model. 54, 1391\u20131400 (2014).","journal-title":"J. Chem. Inf. Model."},{"key":"10026_CR11","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/j.devcel.2005.11.010","volume":"9","author":"S Sazer","year":"2005","unstructured":"Sazer, S. The view from Awaji Island: past, present, and future of RCC1 and the ran GTPase system. Dev. Cell 9, 729\u2013733 (2005).","journal-title":"Dev. Cell"},{"key":"10026_CR12","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/nrm2114","volume":"8","author":"M Stewart","year":"2007","unstructured":"Stewart, M. Molecular mechanism of the nuclear protein import cycle. Nat. Rev. Mol. Cell Biol. 8, 195\u2013208 (2007).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"10026_CR13","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1021\/cb2000296","volume":"6","author":"JF Soderholm","year":"2011","unstructured":"Soderholm, J. F. et al. Importazole, a small molecule inhibitor of the transport receptor importin-\u03b2. ACS Chem. Biol. 6, 700\u2013708 (2011).","journal-title":"ACS Chem. Biol."},{"key":"10026_CR14","doi-asserted-by":"publisher","first-page":"2713","DOI":"10.1007\/s11033-011-1026-5","volume":"39","author":"F Wang","year":"2012","unstructured":"Wang, F. et al. miR-29a and miR-142-3p downregulation and diagnostic implication in human acute myeloid leukemia. Mol. Biol. Rep. 39, 2713\u20132722 (2012).","journal-title":"Mol. Biol. Rep."},{"key":"10026_CR15","doi-asserted-by":"publisher","first-page":"3510","DOI":"10.1158\/0008-5472.CAN-17-3592","volume":"78","author":"MC Trissal","year":"2018","unstructured":"Trissal, M. C. et al. MIR142 loss-of-function mutations derepress ASH1L to increase HOXA gene expression and promote leukemogenesis. Cancer Res. 78, 3510\u20133521 (2018).","journal-title":"Cancer Res."},{"key":"10026_CR16","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1242\/jcs.02787","volume":"119","author":"F Tatin","year":"2006","unstructured":"Tatin, F., Varon, C., Ge\u0301not, E. & Moreau, V. A signalling cascade involving PKC, Src and Cdc42 regulates podosome assembly in cultured endothelial cells in response to phorbol ester. J. Cell Sci. 119, 769\u2013781 (2006).","journal-title":"J. Cell Sci."},{"key":"10026_CR17","doi-asserted-by":"publisher","first-page":"2285","DOI":"10.1038\/s41375-021-01166-9","volume":"35","author":"LXT Nguyen","year":"2021","unstructured":"Nguyen, L. X. T. et al. Cytoplasmic DROSHA and non-canonical mechanisms of MiR-155 biogenesis in FLT3-ITD acute myeloid leukemia. Leukemia 35, 2285\u20132298 (2021).","journal-title":"Leukemia"},{"key":"10026_CR18","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1111\/jcmm.12003","volume":"17","author":"A Qin","year":"2013","unstructured":"Qin, A. et al. MicroRNA-126 regulates the induction and function of CD4(+) Foxp3(+) regulatory T cells through PI3K\/AKT pathway. J. Cell Mol. Med. 17, 252\u2013264 (2013).","journal-title":"J. Cell Mol. Med."},{"key":"10026_CR19","doi-asserted-by":"publisher","first-page":"36614","DOI":"10.18632\/oncotarget.9311","volume":"7","author":"XJ Wu","year":"2016","unstructured":"Wu, X. J. et al. MicroRNA-126-3p suppresses cell proliferation by targeting PIK3R2 in Kaposi\u2019s sarcoma cells. Oncotarget 7, 36614\u201336621 (2016).","journal-title":"Oncotarget"},{"key":"10026_CR20","doi-asserted-by":"publisher","first-page":"5567","DOI":"10.1038\/sj.onc.1207759","volume":"23","author":"K Miyoshi","year":"2004","unstructured":"Miyoshi, K. et al. The sprouty-related protein, spred, inhibits cell motility, metastasis, and rho-mediated actin reorganization. Oncogene 23, 5567\u20135576 (2004).","journal-title":"Oncogene"},{"key":"10026_CR21","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1126\/science.279.5350.509","volume":"279","author":"A Hall","year":"1998","unstructured":"Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509\u2013514 (1998).","journal-title":"Science"},{"key":"10026_CR22","doi-asserted-by":"publisher","unstructured":"Deng, S. et al. PI3K\/AKT signaling tips the balance of cytoskeletal forces for cancer progression. Cancers 14, https:\/\/doi.org\/10.3390\/cancers14071652 (2022).","DOI":"10.3390\/cancers14071652"},{"key":"10026_CR23","doi-asserted-by":"publisher","first-page":"4227","DOI":"10.1158\/0008-5472.CAN-06-3928","volume":"67","author":"ES Clark","year":"2007","unstructured":"Clark, E. S., Whigham, A. S., Yarbrough, W. G. & Weaver, A. M. Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia. Cancer Res. 67, 4227\u20134235 (2007).","journal-title":"Cancer Res."},{"key":"10026_CR24","doi-asserted-by":"publisher","first-page":"3873","DOI":"10.1242\/jcs.051755","volume":"122","author":"A Dovas","year":"2009","unstructured":"Dovas, A. et al. Regulation of podosome dynamics by WASp phosphorylation: implication in matrix degradation and chemotaxis in macrophages. J. Cell Sci. 122, 3873\u20133882 (2009).","journal-title":"J. Cell Sci."},{"key":"10026_CR25","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.ccr.2005.01.006","volume":"7","author":"DF Seals","year":"2005","unstructured":"Seals, D. F. et al. The adaptor protein Tks5\/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells. Cancer Cell 7, 155\u2013165 (2005).","journal-title":"Cancer Cell"},{"key":"10026_CR26","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.ccell.2016.03.015","volume":"29","author":"ER Lechman","year":"2016","unstructured":"Lechman, E. R. et al. miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell 29, 602\u2013606 (2016).","journal-title":"Cancer Cell"},{"key":"10026_CR27","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/s41375-024-02146-5","volume":"38","author":"H Kang","year":"2024","unstructured":"Kang, H. et al. OST-01, a natural product from Baccharis coridifolia, targets c-Myc-dependent ribogenesis in acute myeloid leukemia. Leukemia 38, 657\u2013662 (2024).","journal-title":"Leukemia"},{"key":"10026_CR28","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s40164-024-00586-4","volume":"13","author":"H Kang","year":"2024","unstructured":"Kang, H. et al. AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition. Exp. Hematol. Oncol. 13, 123 (2024).","journal-title":"Exp. Hematol. Oncol."}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10026-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10026-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10026-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T23:30:49Z","timestamp":1781134249000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10026-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["10026"],"URL":"https:\/\/doi.org\/10.1038\/s42003-026-10026-0","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]},"assertion":[{"value":"12 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"791"}}