{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T18:15:33Z","timestamp":1782324933253,"version":"3.54.5"},"reference-count":93,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"content-version":"vor","delay-in-days":68,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-AI148240,T32-AI055428"],"award-info":[{"award-number":["R01-AI148240,T32-AI055428"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,2]]},"abstract":"<jats:p>\n                    The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny are controlled by the JAK\/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (CUL5), can regulate JAK\/STAT signaling by degrading signaling intermediates. Here we report that mice lacking CUL5 in hematopoietic cells (Cul5\n                    <jats:sup>Vav-Cre<\/jats:sup>\n                    ) have increased numbers of hematopoietic stem and progenitor cells (HSPCs), splenomegaly, and extramedullary hematopoiesis. Differentiation in Cul5\n                    <jats:sup>Vav-Cre<\/jats:sup>\n                    mice is myeloid- and megakaryocyte-biased, resulting in leukocytosis, anemia, and thrombocytosis. Cul5\n                    <jats:sup>Vav-Cre<\/jats:sup>\n                    mice had increased HSC proliferation and circulation, associated with a decrease in CXCR4 surface expression. In bone marrow cells, we identified LRRC41 coimmunoprecipitated with CUL5, and vice versa, supporting that CRL5 forms a complex with LRRC41. We identified an accumulation of LRRC41 and STAT5 in Cul5\n                    <jats:sup>Vav-Cre<\/jats:sup>\n                    HSCs during IL-3 stimulation, supporting their regulation by CUL5. Whole-cell proteome analysis of HSPCs from Cul5\n                    <jats:sup>Vav-Cre<\/jats:sup>\n                    bone marrow identified upregulation of many STAT5 target genes and associated pathways. Finally, JAK1\/2 inhibition with ruxolitinib normalized hematopoiesis in Cul5\n                    <jats:sup>Vav-Cre<\/jats:sup>\n                    mice. These studies demonstrate the function of CUL5 in HSC function, stem cell fate decisions, and regulation of IL-3 signaling.\n                  <\/jats:p>","DOI":"10.1172\/jci180913","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T12:00:16Z","timestamp":1750939216000},"source":"Crossref","is-referenced-by-count":7,"title":["The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice"],"prefix":"10.1172","volume":"135","author":[{"given":"Siera A.","family":"Tomishima","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale D.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Porter","sequence":"additional","affiliation":[{"name":"Division of Protective Immunity,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ipsita","family":"Guha","sequence":"additional","affiliation":[{"name":"Division of Protective Immunity,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asif A.","family":"Dar","sequence":"additional","affiliation":[{"name":"Division of Protective Immunity,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohaniz","family":"Ortega-Burgos","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Roof","sequence":"additional","affiliation":[{"name":"Division of Cell Pathology, 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