{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:02:54Z","timestamp":1790251374901,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T00:00:00Z","timestamp":1552867200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:p>Adult long\u2010term hematopoiesis depends on sustaining hematopoietic stem\/progenitor cells (<jats:styled-content style=\"fixed-case\">HSPC<\/jats:styled-content>) in bone marrow (<jats:styled-content style=\"fixed-case\">BM<\/jats:styled-content>) niches, where their balance of quiescence, self\u2010renewal, and hematopoietic differentiation is tightly regulated. Although various <jats:styled-content style=\"fixed-case\">BM<\/jats:styled-content> stroma cells that produce niche factors have been identified, regulation of the intrinsic responsiveness of <jats:styled-content style=\"fixed-case\">HSPC<\/jats:styled-content> to the niche factors remains elusive. We previously reported that mice deficient for <jats:italic>Sipa1<\/jats:italic>, a Rap1 <jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content>ase\u2010activating protein, develop diverse hematopoietic disorders of late onset. Here we showed that transplantation of <jats:styled-content style=\"fixed-case\">BM<\/jats:styled-content> cells expressing membrane\u2010targeted <jats:italic>C3G (C3G\u2010F)<\/jats:italic>, a Rap1 <jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">GDP<\/jats:styled-content> exchanger, resulted in the progressive decline of the numbers of <jats:styled-content style=\"fixed-case\">HSPC<\/jats:styled-content> repopulated in <jats:styled-content style=\"fixed-case\">BM<\/jats:styled-content> with time and impaired long\u2010term hematopoiesis of all cell lineages. <jats:italic>C3G\u2010F<\/jats:italic>\/<jats:styled-content style=\"fixed-case\">HSPC<\/jats:styled-content> were sustained for months in spleen retaining hematopoietic potential, but these cells inefficiently contributed to overall hematopoietic reconstitution. <jats:italic>C3G\u2010F<\/jats:italic>\/<jats:styled-content style=\"fixed-case\">HSPC<\/jats:styled-content> showed enhanced proliferation and differentiation with accelerated progenitor cell exhaustion in response to stem cell factor (<jats:styled-content style=\"fixed-case\">SCF<\/jats:styled-content>). Using a Ba\/F3 cell line, we confirmed that the increased basal Rap1<jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content> levels with <jats:italic>C3G\u2010F<\/jats:italic> expression caused a markedly prolonged activation of c\u2010Kit receptor and downstream signaling through <jats:styled-content style=\"fixed-case\">SCF<\/jats:styled-content> ligation. A minor population of <jats:italic>C3G\u2010F<\/jats:italic>\/<jats:styled-content style=\"fixed-case\">HSPC<\/jats:styled-content> also showed enhanced proliferation in the presence of thrombopoietin (<jats:styled-content style=\"fixed-case\">TPO<\/jats:styled-content>) compared to <jats:italic>Vect<\/jats:italic>\/<jats:styled-content style=\"fixed-case\">HSPC<\/jats:styled-content>. Current results suggest an important role of basal Rap1 activation status of <jats:styled-content style=\"fixed-case\">HSPC<\/jats:styled-content> in their maintenance in <jats:styled-content style=\"fixed-case\">BM<\/jats:styled-content> for sustaining long\u2010term adult hematopoiesis.<\/jats:p>","DOI":"10.1111\/cas.13974","type":"journal-article","created":{"date-parts":[[2019,2,15]],"date-time":"2019-02-15T08:25:11Z","timestamp":1550219111000},"page":"1317-1330","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long\u2010term hematopoiesis"],"prefix":"10.1111","volume":"110","author":[{"given":"Takahiko","family":"Imai","sequence":"first","affiliation":[{"name":"Medical Innovation Center Graduate School of Medicine Kyoto University  Kyoto 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