{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T07:20:40Z","timestamp":1772954440856,"version":"3.50.1"},"reference-count":34,"publisher":"American Society of Hematology","issue":"14","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,4,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The downstream signaling of the interleukin-7 (IL-7) receptor (IL-7R) plays important physiological and pathological roles, including the differentiation of lymphoid cells and proliferation of acute lymphoblastic leukemia cells. Gain-of-function mutations in the IL-7R\u03b1 chain, the specific component of the receptor for IL-7, result in constitutive, IL-7\u2013independent signaling and trigger acute lymphoblastic leukemia. Here, we show that the loss of the phosphoinositide 5-phosphatase INPP5K is associated with increased levels of the INPP5K substrate phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2) and causes an altered dynamic structure of the IL-7 receptor. We discovered that the IL-7R\u03b1 chain contains a very conserved positively charged polybasic amino acid sequence in its cytoplasmic juxtamembrane region; this region establish stronger ionic interactions with negatively charged PtdIns(4,5)P2 in the absence of INPP5K, freezing the IL-7R\u03b1 chain structure. This dynamic structural alteration causes defects in IL-7R signaling, culminating in decreased expressions of EBF1 and PAX5 transcription factors, in microdomain formation, cytoskeletal reorganization, and bone marrow B-cell differentiation. Similar alterations after the reduced INPP5K expression also affected mutated, constitutively activated IL-7R\u03b1 chains that trigger leukemia development, leading to reduced cell proliferation. Altogether, our results indicate that the lipid 5-phosphatase INPP5K hydrolyzes PtdIns(4,5)P2, allowing the requisite conformational changes of the IL-7R\u03b1 chain for optimal signaling.<\/jats:p>","DOI":"10.1182\/blood.2022017819","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T20:16:46Z","timestamp":1672863406000},"page":"1708-1717","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":5,"title":["INPP5K controls the dynamic structure and signaling of wild-type and mutated, leukemia-associated IL-7 receptors"],"prefix":"10.1182","volume":"141","author":[{"given":"Bastien","family":"Mo\u00ebs","sequence":"first","affiliation":[{"name":"1Laboratory of Functional Genetics, GIGA Research Centre, Universit\u00e9 de Li\u00e8ge, Li\u00e8ge, Belgium"}]},{"given":"Hua","family":"Li","sequence":"additional","affiliation":[{"name":"2State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China"}]},{"given":"Patricia","family":"Molina-Ortiz","sequence":"additional","affiliation":[{"name":"1Laboratory of Functional Genetics, GIGA Research Centre, Universit\u00e9 de Li\u00e8ge, Li\u00e8ge, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6254-5258","authenticated-orcid":false,"given":"Coraline","family":"Radermecker","sequence":"additional","affiliation":[{"name":"3Laboratory of Immunophysiology, GIGA Research Centre, Universit\u00e9 de Li\u00e8ge, Li\u00e8ge, Belgium"}]},{"given":"Adeline","family":"Rosu","sequence":"additional","affiliation":[{"name":"4Laboratory of Cellular and Molecular Immunology, GIGA Research Centre, Universit\u00e9 de Li\u00e8ge, Li\u00e8ge, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6283-9029","authenticated-orcid":false,"given":"Charles-Andrew","family":"Vande Catsyne","sequence":"additional","affiliation":[{"name":"1Laboratory of Functional Genetics, GIGA Research Centre, Universit\u00e9 de Li\u00e8ge, Li\u00e8ge, Belgium"}]},{"given":"Sufyan Ali","family":"Sayyed","sequence":"additional","affiliation":[{"name":"1Laboratory of Functional Genetics, GIGA Research Centre, Universit\u00e9 de Li\u00e8ge, Li\u00e8ge, Belgium"}]},{"given":"Jo\u00e3o","family":"Fontela","sequence":"additional","affiliation":[{"name":"5Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1459-161X","authenticated-orcid":false,"given":"Mafalda","family":"Duque","sequence":"additional","affiliation":[{"name":"5Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7498-9841","authenticated-orcid":false,"given":"Alice","family":"Mostafa","sequence":"additional","affiliation":[{"name":"1Laboratory of Functional Genetics, GIGA Research Centre, Universit\u00e9 de Li\u00e8ge, Li\u00e8ge, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2429-2100","authenticated-orcid":false,"given":"Abdelhalim","family":"Azzi","sequence":"additional","affiliation":[{"name":"1Laboratory of Functional Genetics, GIGA Research Centre, Universit\u00e9 de Li\u00e8ge, Li\u00e8ge, Belgium"}]},{"given":"Jo\u00e3o T.","family":"Barata","sequence":"additional","affiliation":[{"name":"5Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5306-0635","authenticated-orcid":false,"given":"Ramon","family":"Merino","sequence":"additional","affiliation":[{"name":"6Instituto de Biomedicina y Biotecnolog\u00eda de Cantabria, CSIC-Universidad de Cantabria-SODERCAN, Santander, Spain"}]},{"given":"Chenqi","family":"Xu","sequence":"additional","affiliation":[{"name":"2State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China"},{"name":"7School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5723-2449","authenticated-orcid":false,"given":"Christophe J.","family":"Desmet","sequence":"additional","affiliation":[{"name":"4Laboratory of Cellular and Molecular Immunology, GIGA Research Centre, Universit\u00e9 de Li\u00e8ge, Li\u00e8ge, 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